Hodgkin Lymphoma - A Comprehensive Overview (2020)

Hematologic Malignancies Series Editor: Martin Dreyling Andreas Engert Anas Younes Editors Hodgkin Lymphoma A Comprehensive Overview Third Edition Hematologic Malignancies Series Editor Martin Dreyling München, Germany Andreas Engert • Anas Younes Editors Hodgkin Lymphoma A Comprehensive Overview Third Edition Editors Andreas Engert Department of Internal Medicine University Hospital Cologne Köln, Nordrhein-Westfalen Germany Anas Younes Lymphoma Service Memorial Sloan Kettering Cancer Center NY, USA ISSN 2197-9766 ISSN 2197-9774 (electronic) Hematologic Malignancies ISBN 978-3-030-32481-0 ISBN 978-3-030-32482-7 (eBook) https://doi.org/10.1007/978-3-030-32482-7 © Springer Nature Switzerland AG 2020 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland Preface Hodgkin lymphoma has become one of the best curable malignancies in both adult and pediatric patients. More than 80% of all patients can be cured with risk-adapted treatment including chemotherapy and radiotherapy. This progress is largely due to the development of multi-agent chemotherapy and the improvements in radiotherapy. Due to the high cure rate and the young age of most patients affected, Hodgkin lymphoma has also become a model for studying long-term toxicity of radiotherapy and chemotherapy that may impact quality of life and/or survival. Future treatment should continue to balance the need for improving the cure rate while reducing treatment-related side effects. In addition, there are a number of relevant physical and psychosocial issues including infertility and fatigue that need to be further exploited. Monoclonal antibodies against this antigen were successfully used for diagnostic immunophenotyping and exploited therapeutically. This strategy has come full circle with the advent of the anti-CD30 antibody drug conjugate Brentuximab Vedotin. This drug has shown remarkable responses in relapsed and refractory classical Hodgkin lymphoma and is also being used in combination with chemotherapy. The development of targeted treatment for patients with Hodgkin lymphoma is rapidly evolving. The recent approval of checkpoint inhibitors has added an additional treatment option for patients with relapsed cHL, opening the door for new developments including new combinations of chemotherapy or radiotherapy being evaluated in first line. This book should give you a comprehensive overview of the most relevant biology, diagnostic and clinical aspects of Hodgkin lymphoma. We would like to express our sincere gratitude to all those who have contributed to this project. Cologne, Germany New York, NY, USA Andreas Engert Anas Younes v Contents Part I Epidemiology and Pathogenesis 1Epidemiology of Hodgkin Lymphoma �� 3 Henrik Hjalgrim and Ruth F. Jarrett 2The Role of Viruses in the Genesis of Hodgkin Lymphoma�� 25 Ruth F. Jarrett, Henrik Hjalgrim, and Paul G. Murray 3Pathology and Molecular Pathology of Hodgkin Lymphoma�� 47 Andreas Rosenwald and Ralf Küppers 4Microenvironment, Cross-Talk, and Immune Escape Mechanisms�� 69 Lydia Visser, Johanna Veldman, Sibrand Poppema, Anke van den Berg, and Arjan Diepstra 5What Have We Learnt from Genomics and Transcriptomics in Classic Hodgkin Lymphoma�� 87 Davide Rossi and Christian Steidl Part II Diagnosis and First-Line Treatment 6Clinical Evaluation�� 99 James O. Armitage and Jonathan W. Friedberg 7Functional Imaging in Hodgkin Lymphoma �� 113 Andrea Gallamini, Bruce Cheson, and Martin Hutchings 8Prognostic Factors�� 145 Paul J. Bröckelmann and Lena Specht 9Principles of Radiation Therapy for Hodgkin Lymphoma�� 171 Joachim Yahalom, Bradford S. Hoppe, Joanna C. Yang, and Richard T. Hoppe 10Principles of Chemotherapy in Hodgkin Lymphoma�� 199 David Straus and Mark Hertzberg 11Treatment of Early Favorable Hodgkin Lymphoma�� 219 Wouter Plattel and Pieternella Lugtenburg vii viii 12Treatment of Early Unfavorable Hodgkin Lymphoma�� 237 Marc P. E. André and Andreas Engert 13Treatment of Advanced-Stage Hodgkin Lymphoma�� 249 Alexander Fosså, René-Olivier Casasnovas, and Peter W. M. Johnson 14Optimizing Decision Making in Hodgkin Lymphoma�� 265 Susan K. Parsons, Joshua T. Cohen, and Andrew M. Evens Part III Special Clinical Situations 15Pediatric Hodgkin Lymphoma�� 277 Georgina W. Hall, Cindy Schwartz, Stephen Daw, and Louis S. Constine 16The Management of Older Patients with Hodgkin Lymphoma�� 297 Boris Böll and Andrew M. Evens 17Nodular Lymphocyte-Predominant Hodgkin Lymphoma �� 317 Dennis A. Eichenauer and Ranjana H. Advani 18The Management of Hodgkin Lymphoma During Pregnancy�� 325 Veronika Bachanova and Joseph M. Connors 19The Management of HIV-Hodgkin Lymphoma�� 335 Marcus Hentrich and Michele Spina Part IV Relapsed and Refractory Disease 20Relapsed and Refractory Hodgkin Lymphoma�� 351 Bastian von Tresckow and Craig Moskowitz 21Allogeneic Transplantation for Relapsed Hodgkin Lymphoma�� 365 Anna Sureda, Martina Pennisi, and Paolo Corradini 22Targeting CD30 in Patients with Hodgkin Lymphoma�� 381 Anita Kumar, Stefano Pileri, Anas Younes, and Andreas Engert 23Hodgkin Lymphoma and PD-1 Blockade�� 395 Reid Merryman, Philippe Armand, and Stephen Ansell 24Other New Agents for Hodgkin Lymphoma�� 411 Alison J. Moskowitz and Anas Younes Part V Survivorship 25Quality of Life in Hodgkin Lymphoma�� 419 Stefanie Kreissl, Hans-Henning Flechtner, and Peter Borchmann Contents Contents ix 26Second Malignancy Risk After Treatment of Hodgkin Lymphoma�� 429 Michael Schaapveld, David C. Hodgson, and Flora E. van Leeuwen 27Cardiovascular and Pulmonary Late Effects�� 465 Berthe M. P. Aleman and David J. Cutter 28Gonadal Dysfunction and Fertility Preservation in Hodgkin Lymphoma Patients �� 485 Karolin Behringer and Michael von Wolff 29Cancer-Related Fatigue in Hodgkin Lymphoma�� 501 Stefanie Kreissl, Anton Hagenbeek, Hans Knoop, and Peter Borchmann Part I Epidemiology and Pathogenesis 1 Epidemiology of Hodgkin Lymphoma Henrik Hjalgrim and Ruth F. Jarrett Contents 1.1 Introduction 4 1.2 Definition and Histological Classification (WHO) 4 1.3 1.3.1 1.3.2 1.3.2.1 1.3.2.2 1.3.2.3 1.3.3 1.3.4 1.3.5 Hodgkin Lymphoma Occurrence Overall Incidence Age-Specific Incidence Patterns Vary Geographically Historical Patterns Modern Age-Specific Incidence Patterns Age-Specific Incidence Patterns for Hodgkin Lymphoma Subtypes Incidence Trends Classifications for Epidemiological Studies: Multi-disease Models Classifications by Age at Diagnosis, Histology and Tumour Epstein-Barr Virus Status Overlap Between Epidemiological Classifications of Hodgkin Lymphoma 1.3.6 amilial Accumulation of Hodgkin Lymphoma: F Genetic Predisposition 1.4.1 Genetic Studies: Genome-Wide Association Studies 1.4.1.1 Hodgkin Lymphoma Subtype-Specific Associations in Genetic Analyses 5 5 5 5 6 7 7 10 10 11 1.4 1.5 isk Factors R 1.5.1 revailing Hypotheses in Hodgkin Lymphoma Epidemiology P 1.5.1.1 Childhood Socio-Economic Environment 1.5.2 Anthropometry 12 12 12 13 13 13 14 H. Hjalgrim (*) Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark Department of Haematology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark e-mail: HHJ@ssi.dk R. F. Jarrett MRC-University of Glasgow Centre for Virus Research, Glasgow, UK © Springer Nature Switzerland AG 2020 A. Engert, A. Younes (eds.), Hodgkin Lymphoma, Hematologic Malignancies, https://doi.org/10.1007/978-3-030-32482-7_1 3 H. Hjalgrim and R. F. Jarrett 4 1.5.3 1.5.3.1 1.5.3.2 1.5.3.3 1.5.3.4 1.5.4 1.5.4.1 1.5.4.2 1.5.4.3 Medical History Infections Primary and Secondary Immune Deficiencies Autoimmune and Allergic Disorders Medications Environmental Exposures Ultraviolet Light Tobacco Alcohol 15 15 16 17 17 18 18 18 18 1.6 Conclusion 19 References 1.1 Introduction The treatment of Hodgkin lymphoma has become one of the great successes in modern oncology with cure rates exceeding 90% for patients with early-stage disease and approaching the same level for patients with advanced disease [1, 2] (see also elsewhere in this book). Although Hodgkin lymphoma was among the first haematological malignancies described in the literature in 1832 [3], the advances made in the understanding of the natural history of Hodgkin lymphoma and its causes are less impressive. It might be ventured that the impressive treatment results leave this to be of little consequence; however, efforts in this regard are continuously worthwhile. Accordingly, the good prognosis for Hodgkin lymphoma is entirely dependent on modern care which is inaccessible in many parts of the world, where the disease still carries considerable mortality. Moreover, as highlighted by a growing literature, the high cure rates have been achieved at the cost of a high frequency of late and often severe adverse treatment effects among Hodgkin lymphoma survivors [4]. Consequently, if better understanding of Hodgkin lymphoma aetiology could help identify means to its prevention, e.g. through vaccination [5], much could be gained. The present chapter gives an overview of the epidemiology of Hodgkin lymphoma and summarizes current understanding of its risk factors. For a more detailed review, please be referred to [6]. 19 1.2 Definition and Histological Classification (WHO) Hodgkin lymphoma is a malignancy which in the vast majority of cases is derived from germinal centre B-lymphocytes, with odd cases (possibly) being of T-cell origin [7]. The current WHO classification recognizes two main variants of Hodgkin lymphoma, specifically classic Hodgkin lymphoma and nodular lymphocytic predominant Hodgkin lymphoma [8, 9]. The two variants of Hodgkin lymphoma display different clinical, morphological, immunological and molecular characteristics, allowing them to be distinguished with reasonable precision [10, 11]. Because the two variants are also believed to have different natural histories, they are conventionally considered separately in epidemiological investigations whenever possible. This is also the case in the present chapter, which for all practical purposes will focus on classic Hodgkin lymphoma. Classic Hodgkin lymphomas make up around 95% of all cases and are further divided into four subtypes referred to as nodular sclerosis (70% of all classic Hodgkin lymphomas), mixed cellularity (20–25% of classic Hodgkin lymphomas), lymphocyte-rich, and lymphocyte-depleted classic Hodgkin lymphoma, respectively [12, 13]. Because the distinction between the classic Hodgkin lymphoma subtypes relies entirely on a subjective interpretation of the histological presentation of the tumour lesion, it is subject to 1 Epidemiology of Hodgkin Lymphoma 5 both inter- and intra-observer variation [10, 11]. While classic Hodgkin lymphoma subtype may previously have had clinical relevance, this is no longer the case with modern imaging tools aiding diagnosis [14]. Importantly, because of the distribution of the Hodgkin lymphoma variants and classic Hodgkin lymphoma subtypes, investigations reporting associations of one kind or another for Hodgkin lymphoma overall will still be epidemiologically informative. As already alluded to the discordant incidence and mortality patterns reflect that modern therapy can cure most Hodgkin lymphoma patients and that access to such therapy is dependent on the level of socio-economic development [16]. Of note, similar socio-economically dependent variation in Hodgkin lymphoma mortality can also be observed in affluent countries [17] and underscores the continued need for epidemiological investigations to promote preventive interventions. 1.3 Hodgkin Lymphoma Occurrence 1.3.2 1.3.1 Overall Incidence 1.3.2.1 Historical Patterns Hodgkin lymphoma occurs at all ages, but among populations, age-specific incidence distributions tend to vary with their ethnic and socio-economic make-up. This variation was summarized into four prototypical incidence patterns (numbered I through IV) in studies in the 1950s, 1960s and 1970s [18–20]. Because they have permeated Hodgkin lymphoma epidemiological thinking for decades, the four patterns are briefly described for the sake of completeness. Pattern I was observed in developing countries and comprised an accumulation of Hodgkin lymphoma cases—predominantly mixed cellularity— among young boys, low incidence throughout the second and third decades of life and increasing incidence with age among older adults. Pattern III was seen in affluent Western countries and demonstrated low incidence in childhood, a marked accumulation of cases—typically nodular sclerosis—in adolescents and younger adults (AYA), a lower incidence in middle-aged adults and an increasing incidence with age among older adults. Pattern II was observed in rural areas of affluent countries and perceived as an intermediate between patterns I and III. Finally, a pattern IV prevailed in Asian countries and featured low incidence rates throughout the first four decades of life followed by increasing incidence with age among older adults. The International Agency for Research on Cancer estimates that world-wide close to 80,000 individuals (33,431 women and 46,559 men) were diagnosed with Hodgkin lymphoma in 2018 and that slightly more than 26,000 individuals (10,397 women and 15,770 men) succumbed to the disease the same year [15]. This places Hodgkin lymphoma as the 27th commonest cancer diagnosed and the 27th commonest cancer-specific cause of death [15]. Both Hodgkin lymphoma incidence and mortality display considerable geographic variation. Overall, Hodgkin lymphoma incidence is higher in Western world industrialized countries than in Asian and developing countries (Fig. 1.1). In the USA, for instance, age-standardized (world population) incidence rates were of the order 2.8 and 2.2 per 100,000 per year in men and women, respectively, whereas the corresponding figures for Indian men and women were 0.79 and 0.58 per 100,000 per year, respectively [15]. Hodgkin lymphoma mortality, conversely, is higher in some developing countries than in industrialized countries (Fig. 1.2). Accordingly, age-standardized mortality rates (world) were 0.25 and 0.14 per 100,000 per year for US men and women, respectively, and 0.53 and 0.35 per 100,000 per year for Indian men and women, respectively [15]. Age-Specific Incidence Patterns Vary Geographically H. Hjalgrim and R. F. Jarrett 6 Estimated age-standardized incidence rates (World) in 2018, Hodgkin lymphoma, both sexes, all ages ASR (World) per 100 000 ≥ 2.1 1.5-2.1 0.78-1.5 0.39-0.78 < 0.39 Not applicable No data Fig. 1.1 Estimated age-standardized incidence rates of Hodgkin lymphoma for both sexes combined (Data from [15]) Estimated age-standardized mortality rates (World) in 2018, Hodgkin lymphoma, both sexes, all ages ASR (World) per 100 000 ≥ 0.53 0.33-0.53 0.23-0.33 0.08-0.23 Not applicable < 0.08 No data Fig. 1.2 Estimated age-standardized mortality rates of Hodgkin lymphoma for both sexes combined (Data from [15]) 1.3.2.2 M odern Age-Specific Incidence Patterns The main features of the prototypical Hodgkin lymphoma incidence patterns, i.e. incidence peaks in boys, AYAs and older adults, are still recognizable. In Chennai, India, for instance, the age- specific Hodgkin lymphoma incidence pattern for the period 1993–2012 displayed a type I-like pattern with a peak in boys less than 10 years of age, no incidence peak among adolescents and younger adults and increasing incidence with age among older adults (Fig. 1.3), even if a transition towards a type II-like pattern can be observed in the more recent of these data [15]. 1 Epidemiology of Hodgkin Lymphoma Of note, an incidence peak among boys can also be demonstrated within European populations when more granular data are available for analysis [21, 22]. In the USA, conversely, Hodgkin lymphoma incidence follows a type III-like pattern with incidence peaks among AYAs and older adults, respectively (Figs. 1.3 and 1.4). Even within the US age-specific incidence patterns adhere to the correlation with socio- economic level. In California, a survey of cases diagnosed 1988–1992 showed higher Hodgkin lymphoma incidence among adolescents and younger adults in the highest compared with the lowest tertile of socio-economic status (Fig. 1.4) [23]. 7 Although it correlates with the level of socio- economic development, the geographical variation in Hodgkin lymphoma incidence likely also reflects an association with ethnicity (Fig. 1.6). Thus, in a Californian survey, variation in Hodgkin lymphoma incidence rates between ethnic/racial groups was apparent even within strata of socio-economic status [23]. 1.3.3 Incidence Trends Changes to Hodgkin lymphoma classification systems have not been substantial in principle allowing analyses of incidence over longer time periods. However, considerable misclassification between Hodgkin and non-Hodgkin lym1.3.2.3 Age-Specific Incidence Patterns phomas in the older age groups (see [10, 11, 24] for Hodgkin Lymphoma and references therein) resulted in inflated Subtypes Hodgkin lymphoma incidence rates in these age The bimodal age distribution of Hodgkin lym- groups in earlier studies. Improvement of diagphoma incidence overall in affluent populations nostic precision may, therefore, contribute to the is largely mirrored by the corresponding distribu- decreasing Hodgkin lymphoma incidence rates tion of the classic Hodgkin lymphoma variants that have been reported in older age groups (e.g. (Fig. 1.5). [24–26]). Both nodular sclerosis and mixed cellularity The misclassification vis-à-vis non-Hodgkin classic Hodgkin lymphoma display bimodal age lymphoma has been less for Hodgkin lymphoma distributions with incidence peaks in AYA and among younger patients, rendering incidence older adult age groups, respectively (Fig. 1.5). trend analyses more meaningful. The correlation Mixed cellularity classic Hodgkin lymphoma between age-specific incidence patterns and level may be the most common subtype among the of socio-economic development in the underlyyoungest children [21], but otherwise nodular ing population strongly suggests that Hodgkin sclerosis classic Hodgkin lymphoma is the most lymphoma occurrence (and risk) is influenced by common subtype in all age groups. environmental factors. More specifically, it indiWhile the age-specific incidence patterns for cates that Hodgkin lymphoma incidence in nodular sclerosis and mixed cellularity Hodgkin childhood and in adolescence and early adultlymphoma overall are similar for the two sexes hood is determined by correlates of socio-ecoand Hodgkin lymphoma incidence overall is nomic status or, alternatively, Westernized higher in men than in women, the incidence of living. classic Hodgkin lymphoma—in effect the noduTherefore, it is perhaps of little surprise that lar sclerosis subtype—may be higher in women increasing incidence of Hodgkin lymphoma has than in men in adolescence and early adulthood been described among adolescents and younger (Fig. 1.3). adults in conjunction with continued improveFor lymphocyte-depleted and lymphocyte- ments in living standards in both industrialized rich classic Hodgkin lymphoma, incidence rates and developing countries (e.g. [25–29]). generally increase with age (Fig. 1.5). Interestingly, the rate of increase appears to have H. Hjalgrim and R. F. Jarrett 8 Fig. 1.3 Age-specific incidence rates for Hodgkin lymphoma in Chennai, India, and in the USA in the period 1993–2012 (Data from Bray F, Colombet M, Mery L, Piñeros M, Znaor A, Zanetti R and Ferlay J, editors (2017) Cancer Incidence in Five Continents, Vol. XI (electronic version) Lyon, IARC. http://ci5. iarc.fr last accessed on [25 March 2019]) Hodgkin Iymphoma (1993-2012) 6.5 6.0 5.5 5.0 4.5 rate per 100,000 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 0- 10- 20- 30- 4050age 60- 70- 80- International Agency for Research on Cancer (IARC) - 25.3.2019 USA, SEER (9 registries) : Male USA, SEER (9 registries) : Female India, Chennai : Male India, Chennai : Female been more pronounced among AYA women than among AYA men. Because diagnostic misclassification also extends to subtypes of classic Hodgkin lymphoma [10, 11] and because the increasing use of non-excisional biopsies for lymphoma diagnosis limits the tumour material available for diagnostic purposes [30], changes in classic Hodgkin lymphoma subtype-specific trends are also difficult to interpret. Epidemiology of Hodgkin Lymphoma Fig. 1.4 Age-specific incidence rates of Hodgkin lymphoma by tertile of neighbourhood socio-economic status, California, 1988–1992 (Figure reproduced from [23]) 9 7 6 5 Rate/100,000 1 4 3 2 1 0 0-4 10-14 20-24 30-34 40-44 50-54 60-64 70-74 80-84 Age at diagnosis Medium High Low 3.5 Incidence per 100,000 per year 3 2.5 2 1.5 1 0.5 0 00–09 yr 10–19 yr 20–29 yr 30–39 yr 40–49 yr 50–59 yr 60–69 yr 70–79 yr 80+ yr Age group Nodular sclerosis Mixed cellularity Lymphocyte depleted Lymphocyte rich Not otherwise specified Fig. 1.5 Age-specific incidence rates of classic Hodgkin lymphoma in both sexes combined by histological subtype in the USA (2000–2011) (Data from US SEER 18. This Figure was reproduced from [6]) H. Hjalgrim and R. F. Jarrett 10 7 Whites Blacks Hispanics Asian/Pacific Islanders Incidence per 100,000 per year 6 5 4 3 2 1 0 00–09 yr 10–19 yr 20–29 yr 30–39 yr 40–49 yr 50–59 yr 60–69 yr 70–79 yr 80+ yr Age group Fig. 1.6 Age-specific incidence rates of classic Hodgkin lymphoma overall in both sexes combined by race/ethnicity in the USA (2008–2012) (Data from US SEER 18. Figure reproduced from [6]) 1.3.4 Classifications for Epidemiological Studies: Multi-disease Models Efforts to unravel causes of Hodgkin lymphoma have been complicated by the strong suspicion that several epidemiologically and etiologically distinct Hodgkin lymphoma variants exist and because efforts to define these have proven exceedingly difficult. 1.3.5 lassifications by Age at C Diagnosis, Histology and Tumour Epstein-Barr Virus Status Intrigued by the bimodal age distribution and by corresponding epidemiological and clinical variation between cases within the age-specific incidence peaks, MacMahon in 1966 [19] proposed that three etiologically heterogeneous Hodgkin lymphoma types existed and that age at diagnosis, specifically 0–14 years, 15–34 years and 50+ years, could be used as a proxy to distinguish between them. MacMahon, moreover, suggested that Hodgkin lymphoma in young adults had an infectious aetiology [19]. As information on Hodgkin lymphoma subtypes, classified using modern criteria, became available for larger patient series, the composition of cases within the incidence peaks (Fig. 1.6) led to the proposal that nodular sclerosis and mixed cellularity Hodgkin lymphoma each captured one of the supposedly etiologically distinct variants. In 1985, Poppema and colleagues were the first to report the presence of Epstein-Barr virus genome products in the malignant Hodgkin/Reed-Sternberg cells in a patient with Hodgkin lymphoma [31]. Nearly 35 years later, we now know that some 30% of Hodgkin lymphomas among adults in affluent Western populations and even more in African and Asian countries are positive for Epstein-Barr virus [32]. We also know that epidemiologically Epstein-Barr virus- positive and Epstein-Barr virus-negative Hodgkin lymphomas differ (reviewed in [33], and further discussed in Chap. 2). Consequently, tumour Epstein-Barr 1 Epidemiology of Hodgkin Lymphoma 11 virus status offers itself as a third way to group classic Hodgkin lymphoma into epidemiologically distinct entities. 1.3.6 miologically specific entities has empirical merit, as will be discussed in the sections below. However, they are sufficiently incongruent to reflect the same phenomenon or subtype. Age at diagnosis displays some overlap with both histology (Fig. 1.5) and tumour Epstein- Barr virus status (Fig. 1.7). However, there is less overlap between tumour Epstein-Barr virus status and histological subtype. While most mixed cellularity classic Hodgkin lymphomas are Epstein-Barr virus-positive and most nodular verlap Between O Epidemiological Classifications of Hodgkin Lymphoma Each of the three proposed means to stratify Hodgkin lymphoma into etiologically and epidea 6 5 Rate/100,000 4 3 2 1 0 20 30 40 50 60 70 Age (years) b 2.5 2.0 Rate/100,000 Fig. 1.7 Age-specific incidence rates for classic Hodgkin lymphoma overall (dotted line), Epstein- Barr virus-negative (squares) and virus- positive (triangles) classic Hodgkin lymphomas. Panel b: Age-specific Epstein- Barr virus-positive classic Hodgkin lymphoma among men (squares) and women (triangles) (Figure reproduced from [10]) 1.5 1.0 0.5 0 20 30 40 50 Age (years) 60 70 H. Hjalgrim and R. F. Jarrett 12 sclerosis classic Hodgkin lymphomas are Epstein-Barr virus-negative, nodular sclerosis classic Hodgkin lymphomas still make up more than half of all Epstein-Barr virus-positive cases [33]. Because Epstein-Barr virus remains the most plausible causal candidate for Hodgkin lymphoma, its incongruence with the tumour histology classification is insufficient grounds for its dismissal. Therefore, age at diagnosis, tumour histology and tumour Epstein-Barr virus status likely represent different elements of Hodgkin lymphoma natural history, emphasizing its complexity. 1.4 Familial Accumulation of Hodgkin Lymphoma: Genetic Predisposition It has been known for more than half a century that Hodgkin lymphomas cluster within families, the earliest investigation indicating an approximately threefold increased risk among Hodgkin lymphoma patients’ first-degree relatives [34]. Subsequent studies with access to larger and even register-based data have largely confirmed this association. The hitherto largest investigation, a Nordic register-based investigation of 57,475 first-degree relatives of 13,922 classic Hodgkin lymphoma patients, yielded an overall standardized incidence ratio of 3.3 (95% confidence interval 2.8–3.9) for familial recurrence, corresponding to a 0.6% lifetime risk of classic Hodgkin lymphoma among patient relatives [35]. Owing to its magnitude, the Nordic study allowed for stratification of analyses by type of family relation and found a standardized incidence ratio of 2.1 (95% confidence interval 1.6–2.6) for the combined group of patient parents and offspring, but 6.0 (95% confidence interval 4.8–7.4) among patient siblings [35]. Even more extremely increased risks were observed for same-sex twins (standardized incidence ratio 57 (95% confidence interval 21–125)), consistent with the results of a previous American twin study [36]. Hodgkin lymphoma also clusters with other haematological malignancies, notably chronic lymphocytic leukaemia [37] and diffuse large B-cell lymphoma [38], with relative risks for these malignancies being slightly less increased— twofold—than for classic Hodgkin lymphoma. 1.4.1 enetic Studies: Genome- G Wide Association Studies The accumulation of Hodgkin lymphomas among relatives must reflect shared environmental and constitutional risk factors. Both candidate gene investigations and genome-wide association studies confirm the suspicion that genetic predisposition is important to Hodgkin lymphoma risk. The histological presentation of Hodgkin lymphoma is dominated by admixture of accessory and inflammatory cells indicating that immune function is important to the disease. Early research, therefore, focused on the association between tissue type, i.e. HLA, and Hodgkin lymphoma risk. Indeed, Hodgkin lymphoma was among the first diseases linked with markers of specific HLA types [39, 40]. Genotyping of more than 5000 patients with Hodgkin lymphoma has identified a total of 18 genetic loci associated with Hodgkin lymphoma risk. Based on these loci, Sud and colleagues point to three key biological processes underlying Hodgkin lymphoma susceptibility. These are (1) the germinal centre reaction (2p16.1, REL; 3q28, BCL6 and mir-28; 6p21, HLA; 6q23.3, MYB; 8q24.21, MYC; 11q23.1, POU2AF1; 16p11.2, MAPK3; 19p13.3, TCF3; 20q13.12, CD40), (2) T-cell differentiation and function (3p24.1, EOMES; 5q31,1, IL13; 6q22.33, PTPRK and THEMIS; 6q23.3, MYB; 6q23.3, AHI1; 10p14, GATA3; 16p13.1, SOCS1 and CLEC16A; 16p11.2, MAPK3 and CORO1A) and (3) constitutive NF-kB activation (2p16.1, REL; 3p24.1, AZI2; 6q23.3, TNFAIP3; 20q13.12, CD40) [41]. 1.4.1.1 H odgkin Lymphoma Subtype- Specific Associations in Genetic Analyses In addition to shedding light on possible mechanisms underpinning Hodgkin lymphoma pathogenesis in general (discussed in the following 1 Epidemiology of Hodgkin Lymphoma chapter (The Role of Viruses in the Genesis of Hodgkin Lymphoma)), the genetic investigations also add further credence to the notion of etiological heterogeneity between classic Hodgkin lymphoma subtypes. Accordingly, as discussed in the following chapter, evidence is mounting that risk of EpsteinBarr virus-positive Hodgkin lymphoma is strongly associated with alleles in the HLA class I region (e.g. rs2734986, HLA-A; rs6904029, HCG9), whereas risk of Epstein-Barr virus-negative disease is more strongly associated with alleles within the HLA class II region (e.g. rs6903608, HLA-DRA) [42]. The variation in genetic associations underscores the importance of detailed phenotyping in genome-wide association as well as other types of studies of Hodgkin lymphoma. Thus, in the absence of information on either tumour histology or tumour Epstein-Barr virus status, neither the presence nor absence of associations can be fully interpreted. This is illustrated by an extended analysis of the HLA region in the first GWAS to stratify cases by EBV status [42, 43]. This study revealed a single nucleotide polymorphism near the HLA-DPB1 gene (rs6457715) which was associated with Epstein-Barr virus-positive (odds ratio 2.33 (95% confidence interval 1.83– 2.97; P 10–12)), but not with Epstein-Barr virus-negative Hodgkin lymphoma risk (odds ratio 1.06 (95% confidence interval 0.92–1.21); Phom = 10−8), a difference that was present even within strata defined by classic Hodgkin lymphoma histology [43]. With that reservation, the association with class I alleles for Epstein-Barr virus-positive Hodgkin lymphomas or with mixed cellularity Hodgkin lymphoma suggests that cytotoxic T-cells’ control of virally infected lymphocytes whether before or after malignant transformation is significant to the risk of the lymphoma. Epstein-Barr virus-negative Hodgkin lymphoma’s association with HLA class II alleles may reflect a similar role of immune control of an infectious agent in the pathogenesis of this Hodgkin lymphoma subtype. Alternatively, it may also be indicative of the involvement of 13 CD4-positive T follicular helper cells in Hodgkin lymphoma pathogenesis [44]. For further discussion, please be referred to Chap. 2. 1.5 Risk Factors 1.5.1 Prevailing Hypotheses in Hodgkin Lymphoma Epidemiology As already mentioned, for more than half a century, it has been assumed that Hodgkin lymphomas in children, AYA and older adults differ epidemiologically—possibly aetiologically— from one another [19]. Therefore, epidemiological investigations have conventionally considered risk factors for Hodgkin lymphoma for the three age groups separately, when practically possible. Owing to the bimodal age distribution of Hodgkin lymphoma in affluent populations, the epidemiology of AYA Hodgkin lymphoma has been the most studied. 1.5.1.1 Childhood SocioEconomic Environment The correlation between age-specific Hodgkin lymphoma incidence patterns and level of socio-economic development in the underlying population led to the formulation of the socalled late infection model for Hodgkin lymphoma [45, 46]. This model suggests that Hodgkin lymphoma among children, adolescents and younger adults is caused by an infectious agent and that lymphoma risk increases with increasing age at primary infection [45, 46]. Early studies supported this understanding of AYA Hodgkin lymphoma indirectly by reporting that correlates of childhood socio-economic affluence, which are thought to be associated with low childhood infectious disease pressure, such as length of maternal education, home ownership and being a member of a small sibship, were associated with increased risk of AYA Hodgkin lymphoma [47]. Moreover, within sib- H. Hjalgrim and R. F. Jarrett 14 ships, Hodgkin lymphoma risk correlated inversely with number of older siblings, i.e. birth order [47]. Mack and colleagues recently (2015) reported the results of a register-based case-control study nested in a cohort of US army conscripts in the period 1950–1968. The study included 656 men diagnosed with Hodgkin lymphoma at ages 17–32 years and individually matched controls. In univariate analyses, they found increased Hodgkin lymphoma risk with small sibship size (odds ratio 1.4 (95% confidence interval 1.1–1.9) for 2–3 vs. >3 children), birth order (odds ratio 1.9 (95% confidence interval 1.4–2.6) for first vs. middle born) and short age gap to nearest sibling (odds ratio 2.1 (95% confidence interval 1.5–3.1) for more vs. less than 5 years) [48]. Information on histological subtype was available for a subset of the cases in the study of US conscripts, but analyses did not point to different associations for nodular sclerosis and mixed cellularity Hodgkin lymphoma. No information on tumour Epstein-Barr virus status was available for analyses [48]. In later investigations—that is, studies of patients diagnosed in more recent years—the association between traditional measures of childhood socio-economic affluence and AYA Hodgkin lymphoma risk in Western countries has been less compelling or even absent [49–54]. This change in the epidemiology of Hodgkin lymphoma in AYA may suggest that family or rather sibship structure no longer reflects the early life exposures associated with the disease [51]. Of note in this regard, in two case-control investigations, one American and one Scandinavian, kindergarten attendance was associated with reduced Hodgkin lymphoma risk in AYAs (odds ratio 0.64 (95% confidence interval 0.45–0.92) and odds ratio = 0.78 (95% confidence interval 0.56–1.09)) [49, 52]. Information on tumour Epstein-Barr virus status was available in both investigations, and while no differences in association with nursery school attendance were observed in the American investigation, it tended to be stronger for virus-negative Hodgkin lymphoma in the Scandinavian study [49, 52]. This contrast highlights that varying associations may simply result from the subtype composition of the studied Hodgkin lymphomas. The evidence supporting the idea that childhood socio-economic environment influences Hodgkin lymphoma risk in childhood is also insubstantial. One Danish register cohort study found that risk of Hodgkin lymphoma before age 15 years increased with sibship size and birth order [55]. This association was reproduced in neither Swedish [56] nor American data [57]. However, a large North American case-control investigation reported findings similar to the Danish study: increasing sibship size was positively and increasing maternal education and household income inversely associated with Hodgkin lymphoma risk before age 15 years [58]. 1.5.2 Anthropometry Hodgkin lymphoma risk up to the age of early adulthood in some investigations (though not all) associates with increasing birth weight (e.g. [53, 54]). In a Californian register-based investigation, Hodgkin lymphoma risk in the age group 0–19 years was found to increase by 16% (95% confidence interval 1.03–1.30) per kilogram increase in birth weight [54]. While in this investigation the association appeared specific to nodular sclerosis classic Hodgkin lymphoma [54], it applied to both nodular sclerosis and mixed cellularity classic Hodgkin lymphoma in the other [53]. Like reports of association between stature late in childhood/in early adolescence and subsequent risk of Hodgkin lymphoma [59, 60], the association with birth weight may at least in part reflect Hodgkin lymphomas association with childhood socio-economic affluence. A number of prospective investigations have pointed to an association between obesity and Hodgkin lymphoma risk [61–63]. For example, in the UK Million Women Study, body mass index correlated with Hodgkin lymphoma risk (hazard ratio 1.64 (95% confidence interval 1.21– 2.21) per 10 kg per square meter increase)) [63]. If true, the association between obesity and Hodgkin lymphoma risk could reflect obesity- related inflammation references. 1 Epidemiology of Hodgkin Lymphoma 1.5.3 Medical History 15 extension of the Scandinavian cohort study mentioned above, according to which infectious mononucleosis was associated with an increased 1.5.3.1 Infections The late infection model fostered much interest risk of Epstein-Barr virus-positive classic in the search for infectious agents that might Hodgkin lymphomas (standardized incidence cause Hodgkin lymphoma. Among suspected ratio 4.0 (95% confidence interval 3.4–4.5)) and organisms, the human herpesvirus Epstein-Barr not Epstein-Barr virus-negative classic Hodgkin virus, first isolated from Burkitt lymphoma tissue lymphoma (standardized incidence ratio 1.5 [64] and soon after established as the cause of (95% confidence interval 0.9–2.5)) [68]. While similar subtype-specific observations infectious mononucleosis [65], has long been the were also made in British and Scandinavian case- centre of attention. control investigations [49, 69], other studies have reported increased risks for both Epstein-Barr Epstein-Barr Virus Infection: Infectious virus-positive and Epstein-Barr virus-negative Mononucleosis Epidemiological, serological and molecular- Hodgkin lymphomas [70] or no associations at biological (i.e. the presence of Epstein-Barr virus all [50, 52]. genome products in the malignant cells) evidence link Epstein-Barr virus infection to Hodgkin Epstein-Barr Virus Infection: Serological lymphoma development. Here, only the epide- Evidence miological and serological evidence will be pre- Support for the association between Epstein-Barr sented; for the presence and role of Epstein-Barr virus infection and Hodgkin lymphoma risk also comes from serological investigations [71, 72]. virus in the malignant cells, please see Chap. 2. In 1989 Nancy Mueller and colleagues in a Infectious mononucleosis is rarely seen prospective nested case-control study found that among children but is a common presentation of primary infection with the Epstein-Barr virus aberrant patterns of anti-Epstein-Barr virus antiwhen it is delayed until adolescence [66]. bodies were associated with overall Hodgkin Numerous investigations have assessed the asso- lymphoma risk [73]. Three decades later this study was replicated ciation between infectious mononucleosis and Hodgkin lymphoma, and most have reported only this time with information on tumour increased Hodgkin lymphoma risk in the wake of Epstein-Barr virus status. Comparing pre- diagnostic antibody patterns in 40 and 88 infectious mononucleosis (reviewed in [33]). The largest of these was a Scandinavian patients with Epstein-Barr virus-positive and Barr virus-negative classic Hodgkin register-based cohort study of more than 40,000 Epstein- patients with infectious mononucleosis followed lymphomas with those in matched controls, for the occurrence of Hodgkin lymphoma. Levin and colleagues showed that an inverted EBNA2 antibody level ratio Compared with the general population, the infec- anti-EBNA1/anti- tious mononucleosis patients were at a 2.55 (95% (≤1) consistent with impaired control of confidence interval 1.87–3.40)-fold increased Epstein-Barr virus infection was associated with Hodgkin lymphoma risk. The risk increase was a 4.7 (95% confidence interval 1.6–13.8)-fold particularly high shortly after the Epstein-Barr increased risk of Epstein-Barr virus-positive virus infection but remained increased for up to Hodgkin lymphoma, whereas no association negative 20 years of follow-up [67]. Because infectious was observed for Epstein-Barr virus- mononucleosis typically occurs in adolescence, Hodgkin lymphoma [74]. the increased Hodgkin lymphoma risk tended to Epstein-Barr Virus Infection: Variation present in younger adults. In a few investigations, information on in Tumour Prevalence Hodgkin lymphoma Epstein-Barr virus status has Epstein-Barr virus can, as already mentioned, be been available for analyses. One such was an demonstrated in the malignant cells in a proportion 16 of classic Hodgkin lymphomas [32]. Importantly, however, its presence is non-randomly distributed between cases and tends to reflect ethnic, sociodemographic, age, sex and disease-specific circumstances, adding further support to the suspicion of a causal relation. This variation was most eloquently demonstrated by Glaser and colleagues in a pooled analysis of 1546 patients [75]. The analysis showed that irrespective of age at diagnosis, Epstein-Barr virus could more often be demonstrated in mixed cellularity than in nodular sclerosis Hodgkin lymphoma, in children from deprived rather than affluent settings and in male than in female patients, except among older adults. At the same time, compared with adolescents and younger adults, Hodgkin lymphomas in children and older adults were more often Epstein-Barr virus- positive [75]. The seminal paper by Glaser and colleagues once again underscores the importance of information on histological subtype and tumour Epstein-Barr virus status in epidemiological investigations. H. Hjalgrim and R. F. Jarrett phoma has so far been in vain (see also Chap. 2). Indeed, direct support for the decreased infectious disease load in early childhood among adolescent and younger adult Hodgkin lymphoma patients implied by the late infection hypothesis is scarce. Even if in interview-based case-control studies self-reported history of infections such as measles, mumps and rubella have been associated with reduced risk of Hodgkin lymphoma in adolescence and early adulthood [50, 69, 77, 78], the validity of such recalled childhood health history may be questioned. Still, in Mack and colleagues’ prospective study of army conscripts, history of mumps ascertained at the start of follow-up also was associated with reduced Hodgkin lymphoma risk [48]. Cozen and colleagues retrospectively assessed childhood exposures likely to produce oral exposure to microbes among 188 sets of twins discordant for Hodgkin lymphoma diagnosed at ages 13–50 years. Most interestingly, their study showed that Hodgkin lymphoma risk was lower for the twins whose behaviour mostly likely led to oral microbial exposure [79]. A Four-Disease Model for Hodgkin 1.5.3.2 Primary and Secondary Immune Deficiencies Lymphoma The age-dependent variation in prevalence of Similar to non-Hodgkin lymphomas, Hodgkin Epstein-Barr virus-positive Hodgkin lymphomas lymphomas also occur excessively among along with its association with infectious mono- patients suffering from (certain) primary and secnucleosis has given rise to the four-disease model, ondary immune deficiencies (reviewed in [80]). according to which Epstein-Barr virus-positive Risk of Hodgkin lymphoma is between 4- and and Epstein-Barr virus-negative Hodgkin lym- 16-fold increase in cohort studies of HIV-infected phomas are etiologically separate entities [76]. people and between 2- and 7-fold increase in The model is further discussed in Chap. 2, but in cohort studies of solid organ transplant recipients summary suggests that Epstein-Barr virus- (reviewed in [80]). positive Hodgkin lymphoma develops in conMost Hodgkin lymphoma occurring in the setjunction to primary infection with the virus ting of immune deficiency is Epstein-Barr virus- (children and adolescents) or because of subse- positive [80]. Correspondingly, in one cohort quent loss of control with the viral infection in its study of people with AIDS-related immune defichronic phase owing to immune impairment for a ciency, risk was more increased for mixed celluvariety of reasons, while no causes for Epstein- larity (rate ratio 18.3 (95% confidence interval Barr virus-negative Hodgkin lymphoma are 15.9–20.9)) and lymphocyte-depleted (rate ratio suggested. 35.3 (95% confidence interval 24.7–48.8)) Hodgkin lymphoma subtypes than for nodular Other Childhood Infections sclerosis Hodgkin lymphoma [81]. The search for other specific childhood infections There is (some) evidence that Hodgkin lymcausally associated with classic Hodgkin lymphoma risk correlates inversely with degree of 1 Epidemiology of Hodgkin Lymphoma immune suppression as measured by CD4- lymphocyte count among HIV-infected people, but the correlation is less strong than for non- Hodgkin lymphoma and, in contrast to the latter, risk does not correlate with measures of HIV load [82, 83]. These differences between Hodgkin and non- Hodgkin lymphoma may explain why the overall incidence of Hodgkin lymphoma has not decreased to the same extent as non-Hodgkin lymphoma following the introduction of highly active antiviral therapy (see [82] and references therein). 1.5.3.3 Autoimmune and Allergic Disorders Autoimmune and Allergic/Atopic Diseases Several studies have reported an increased risk of Hodgkin lymphoma among patients with autoimmune diseases (see reviews [80, 84]). A large Swedish investigation reported a twofold increased risk of Hodgkin lymphoma risk among 878,000 patients registered with any of 33 autoimmune conditions in the Swedish inpatient register [85]. Temporal variation in relative risk of Hodgkin lymphoma suggested that the increased risk was partially explained by reversed causality; specifically, that incipient (undiagnosed) Hodgkin lymphoma led to autoimmune disease diagnosis. Thus, the standardized incidence ratio (SIR) for Hodgkin lymphoma decreased with time since autoimmune disease diagnosis from 5.2 (95% confidence interval 4.2–6.3) in the first year of follow-up to 2.0 (95% confidence interval 1.7– 2.4) in the period 1–4 years after autoimmune disease diagnosis and to 1.5 (1.2–1.7) at 5 or more years after autoimmune disease diagnosis [85]. Accordingly, when the first 5 years after autoimmune diagnosis was disregarded, statistically significantly increased risk of Hodgkin lymphoma was observed for patients with rheumatoid arthritis (SIR = 2.0 (95% confidence interval 2.1–3.7)), autoimmune haemolytic anaemia (SIR = 16.6 (95% confidence interval 3.1–49.2)), Behcet disease (SIR = 4.0 (95% confidence interval 1.3–9.3)) and systemic lupus erythematosus (SIR = 4.1 (95% confidence interval 1.5–9.0)). Elevated risk estimates, albeit not statistically 17 significant, were still observed for various other autoimmune diseases [85]. The mechanisms underlying the association between Hodgkin lymphoma and autoimmune diseases have remained elusive. Interestingly, in another register-based study from Sweden, reduced risk of Hodgkin lymphoma was observed in families of patients with acute glomerular nephritis, ankylosing spondylitis and Graves disease and increased in family members of patients with pemphigus. In first-degree relatives of Hodgkin lymphoma patients, several autoimmune diseases occurred in excess (Behcet disease, dermatitis herpetiformis, multiple sclerosis, primary biliary cirrhosis and rheumatoid arthritis) or in deficit (celiac disease and psoriasis) pointing to some form of shared risk between the two disease groups [86], which to some extent could be genetic in nature [87]. Multiple sclerosis stands out from other autoimmune diseases in this regard. Thus, studies have shown that Hodgkin lymphoma in young adults and multiple sclerosis clusters mutually within individuals [88] and within families [86, 89]. Moreover, the two conditions have also been found to share genetic risk profiles to the extent that polygenic risk scores for either of the two diseases are associated with risk of the other [87]. Interestingly, these two disparate conditions both share the association with infectious mononucleosis, raising the possibility that the three conditions are somehow immunologically related. Few studies have examined the association between allergic/atopic diseases and Hodgkin lymphoma risk ([90], review in [91]). Methodological issues aside, the results of the analyses are too heterogeneous to preclude conclusions other than that the current evidence does not support any association between the two. In agreement with this, Levin and colleagues found no evidence of an association between pre- diagnostic titres of IgE and Hodgkin lymphoma risk in a prospective serological investigation [92]. 1.5.3.4 Medications Regular use of aspirin has been suggested to be associated with reduced Hodgkin lymphoma risk in one American [93] and in two partly H. Hjalgrim and R. F. Jarrett 18 overlapping Danish studies [94]. Combining the two sets of results in a meta-analysis, long-term use of aspirin was associated with an odds ratio of 0.62 (95% confidence interval 0.46–0.82) for Hodgkin lymphoma [94]. Aspirin’s interference with inhibition of NF-κB which is constitutively active in the malignant Hodgkin/Reed-Sternberg cells and its binding to cyclooxygenase (COX)-1 and cyclooxygenase-2, which are overexpressed in Hodgkin lymphoma, both lend biological plausibility to the observed association [93, 94]. Of note, the same investigations also reported increased Hodgkin lymphoma risk among users of other nonsteroidal anti-inflammatory drugs such as selective Cox-2 inhibitors or acetaminophen. However, temporal variation in the risk increase suggested that reverse causality—confounding by indication—most likely accounted for the observed association [93, 94]. 1.5.4 Environmental Exposures 1.5.4.1 Ultraviolet Light Recent decades have witnessed considerable epidemiological interest in the possible association between vitamin D and cancer because of the vitamin’s potential anticarcinogenic effects [95]. Because ultraviolet light radiation is critical to vitamin D production, studies have typically focused on this exposure, as is also the case for Hodgkin lymphoma investigations. An association between ultraviolet radiation exposure and Hodgkin lymphoma risk is supported by two types of evidence. Firstly, according to ecological studies, Hodgkin lymphoma incidence rates and ambient levels of ambient ultraviolet radiation correlate inversely [96, 97]. Secondly, according to a pooled analysis of data from four case-control studies including a total of 1320 patients with Hodgkin lymphoma and 6381 controls, history of sunburn (odds ratio = 0.77 (95% confidence interval 0.63–0.95)) and sunlamp use (odds ratio = 0.81 (95% confidence interval 0.69–0.96)) and cumulative lifetime exposure to ultraviolet radiation were each associated with statistically significantly decreased risk of Hodgkin lymphoma [98]. The observed associations tended to be stronger for Epstein-Barr virus-positive than for Epstein-Barr virus-negative Hodgkin lymphomas [98]. Both the ecological and the analytical epidemiological data are compatible with ultraviolet radiation exposure in some way or other preventing Hodgkin lymphoma pathogenesis. 1.5.4.2 Tobacco Considering tobacco’s many effects on the human immune system, it is conceivable that it is also associated with Hodgkin lymphoma risk [99]. Support for this notion comes from two meta- analyses and a pooled analysis of several large datasets. The meta-analyses both conclude that current smoking carries a statistically significant 30–40% increased risk of Hodgkin lymphoma [100, 101], whereas the pooled analyses suggest a statistically nonsignificant 16% increased risk [102]. Both meta-analyses also find evidence of doseresponse associations between Hodgkin lymphoma risk and current cigarette smoking measured as number of cigarettes smoked, years smoked and pack-years [100, 101]. The pooled analysis, in contrast, found no evidence of a dose-response pattern in the association between Hodgkin lymphoma risk and cigarette smoking [102]. In stratified analyses, the association with current smoking was stronger for mixed cellularity than for nodular sclerosis Hodgkin lymphoma [100] and correspondingly also stronger for Epstein-Barr virus-positive than for Epstein-Barr virus-negative Hodgkin lymphoma [101, 102]. 1.5.4.3 Alcohol A reduced Hodgkin lymphoma risk with alcohol intake has been suggested by most investigations of the topic, even if observed associations do not always reach statistical significance and rarely display dose-response patterns [103–112]. In a recent meta-analysis of available cohort studies, ever drinking alcohol was associated with a statistically nonsignificant reduced Hodgkin lymphoma risk (relative risk = 0.74 (95% confidence interval 0.52–1.05)) [113]. Although results vary between studies, the reported inverse association has been reported for 1 Epidemiology of Hodgkin Lymphoma 19 all Hodgkin lymphoma subgroups, i.e. for both perspective of the understanding of what drives younger and older adult patients, for Epstein- Hodgkin lymphoma development, this represents Barr virus-positive and Epstein-Barr virus- a field of research that has only been little explored negative Hodgkin lymphoma, as well as for in Epstein-Barr virus status-specific contexts. nodular sclerosis and mixed cellularity Hodgkin The favourable prognosis of Hodgkin lymlymphoma alike. phoma achievable with modern therapy is One caveat to the interpretation of the observed unlikely to foster clinical interest into the clinical reduced Hodgkin lymphoma risk is that the lym- significance of tumour Epstein-Barr virus status phoma may be accompanied by alcohol intoler- or other (potential) markers of baseline treatment ance [114]. Consequently, reduced alcohol intake needs. Accordingly, though it could further could result from early Hodgkin lymphoma man- access to large dataset amenable for research, the ifestations. An attempt to mitigate this problem motivation to determine epidemiologically relewas introduced in the UK Million Study in which vant markers in clinical trials is modest. an increased risk of Hodgkin lymphoma among never drinkers (hazard rate ratio = 1.70 (95% confidence interval 1.27–2.26)) compared with References occasional drinkers (0.5–3 drinks weekly) was 1. Engert A, Haverkamp H, Kobe C et al (2012) unaffected when the first 3 years of follow-up Reduced-intensity chemotherapy and PET-guided was disregarded [112]. Still, this study also radiotherapy in patients with advanced stage showed no dose-response pattern between alcoHodgkin’s lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial. Lancet hol consumption and Hodgkin lymphoma risk. 1.6 Conclusion Studies have demonstrated that Hodgkin lymphomas occurring at different ages have different epidemiologic profiles. This variation is commonly interpreted as evidence that Hodgkin lymphoma comprises two or more aetiologically heterogeneous conditions. Age, histological presentation and tumour Epstein-Barr virus status have been suggested to identify unique classic Hodgkin lymphoma entities. Evidence is strong that Epstein-Barr virus- positive Hodgkin lymphomas are aetiologically different from their Epstein-Barr virus-negative counterparts. There is also good evidence that the risk of Epstein-Barr virus-positive Hodgkin lymphoma at different ages to a large extent is influenced by circumstances influencing age at primary infection and immunological response to or control of the infection, whether in its acute or chronic phases. Meanwhile, the causes of Epstein-Barr virus-negative Hodgkin lymphoma have remained elusive and call for continued research. Both Epstein-Barr virus-positive and Epstein- Barr virus-negative Hodgkin lymphoma can have different histopathological presentations. From the 379(9828):1791–1799 2. Engert A, Plütschow A, Eich HT et al (2010) Reduced treatment intensity in patients with early-stage Hodgkin’s lymphoma. N Engl J Med 363(7):640–652 3. Hodgkin T (1832) On some morbid appearances of the absorbent glands and spleen. Med Chirurg Trans 17:68–114 4. Ng AK, van Leeuwen FE (2016) Hodgkin lymphoma: late effects of treatment and guidelines for surveillance. Semin Hematol 53(3):209–215 5. Cohen JI (2018) Vaccine development for Epstein- Barr virus. Adv Exp Med Biol 1045:477–493 6. Hjalgrim H, Chang ET, Glaser SL (2018) Hodgkin lymphoma. Schottenfeld and Fraumeni Cancer Epidemiology and Prevention. Oxford University Press:745–766 7. Stein H (2001) Hodgkin lymphomas: introduction. WHO Classif Tumours Tumours Haematop Lymphoid Tissues 8:239 8. Stein H, Delsol G, Pileri S et al (2001) Nodular lymphocyte predominant Hodgkin lymphoma. WHO Classif Tumours Tumours Haematopoietic Lymphoid Tissues:240–243 9. Stein H, Delsol G, Pileri S et al (2001, 2001) Classical Hodgkin lymphoma. WHO Classif Tumours Tumours Haematopoietic Lymphoid Tissues:244–253 10. Jarrett RF, Krajewski AS, Angus B et al (2003) The Scotland and Newcastle epidemiological study of Hodgkin’s disease: impact of histopathological review and EBV status on incidence estimates. J Clin Pathol 56(11):811–816 11. Glaser SL, Dorfman RF, Clarke CA (2001) Expert review of the diagnosis and histologic classification H. Hjalgrim and R. F. Jarrett 20 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. of Hodgkin disease in a population-based cancer registry: interobserver reliability and impact on incidence and survival rates. Cancer 92(2):218–224 Stein H, von Wasielewski R, Poppema S, MacLennan K, Guenova M (2008) Nodular sclerosis classical Hodgkin lymphoma. WHO Classif Tumours Tumours Haematopoietic Lymphoid Tissues 2008:330 Weiss LM, von Wasielewski R, Delsol G, Poppema S, Stein H (2008) Mixed cellularity classical Hodgkin lymphoma. WHO Classif Tumours Tumours Haematopoietic Lymphoid Tissues 2008:331 Ansell SM (2015) Hodgkin lymphoma: diagnosis and treatment. Mayo Clin Proc 90(11):1574–1583 Ferlay J, Ervik M, Lam F, Colombet M, Mery L, Piñeros M, Znaor A, Soerjomataram I, Bray F (2018). Global Cancer Observatory: Cancer Today. Lyon, France: International Agency for Research on Cancer. Available from: https://gco.iarc.fr/today, accessed [25 March 2019]. Chatenoud L, Bertuccio P, Bosetti C et al (2013) Hodgkin’s lymphoma mortality in the Americas, 1997–2008: achievements and persistent inadequacies. Int J Cancer 133(3):687–694 Keegan THM, DeRouen MC, Parsons HM et al (2016) Impact of treatment and insurance on socioeconomic disparities in survival after adolescent and young adult Hodgkin lymphoma: a population- based study. Cancer Epidemiol Biomark Prev 25(2):264–273 Macmahon B (1958) Epidemiological evidence of the nature of Hodgkin’s disease. Cancer 10(5):1045–1054 MacMahon B (1966) Epidemiology of Hodgkin’s disease. Cancer Res 26(6):1189–1201 Correa P, O’Conor GT (1971) Epidemiologic patterns of Hodgkin’s disease. Int J Cancer 8(2):192–201 Clavel J, Steliarova-Foucher E, Berger C, Danon S, Valerianova Z (2006) Hodgkin’s disease incidence and survival in European children and adolescents (1978–1997): report from the automated Cancer information system project. Eur J Cancer 42(13):2037–2049 Hjalgrim LL, Rostgaard K, Engholm G et al (2016) Aetiologic heterogeneity in pediatric Hodgkin lymphoma? Evidence from the Nordic countries, 1978– 2010. Acta Oncol (Stockholm) 55(1):85–90 Clarke CA, Glaser SL, Keegan THM, Stroup A (2005) Neighborhood socioeconomic status and Hodgkin’s lymphoma incidence in California. Cancer Epidemiol Biomark Prev 14(6):1441–1447 Glaser SL, Swartz WG (1990) Time trends in Hodgkin’s disease incidence. The role of diagnostic accuracy. Cancer 66(10):2196–2204 Hjalgrim H, Askling J, Pukkala E et al (2001) Incidence of Hodgkin’s disease in Nordic countries. Lancet 358:297–298 van Leeuwen MT, Turner JJ, Joske DJ et al (2014) Lymphoid neoplasm incidence by WHO subtype in Australia 1982–2006. Int J Cancer 135(9):2146–2156 27. Hjalgrim H, Seow A, Rostgaard K, Friborg J (2008) Changing patterns of Hodgkin lymphoma incidence in Singapore. Int J Cancer 123(3):716–719 28. Zhu C, Bassig BA, Shi K et al (2014) Different time trends by gender for the incidence of Hodgkin’s lymphoma among young adults in the USA: a birth cohort phenomenon. Cancer Causes Control 25(8):923–931 29. Aben KK, van Gaal C, van Gils NA, van der Graaf WT, Zielhuis GA (2012) Cancer in adolescents and young adults (15–29 years): a population-based study in the Netherlands 1989–2009. Acta Oncol (Stockholm) 51(7):922–933 30. Glaser SL, Clarke CA, Keegan THM, Chang ET, Weisenburger DD (2015) Time trends in rates of Hodgkin lymphoma histologic subtypes: true incidence changes or evolving diagnostic practice? Cancer Epidemiol Biomark Prev 24(10):1474–1488 31. Poppema S, Van Imhoff G, Torensma R, Smit J (1985) Lymphadenopathy morphologically consistent with Hodgkin’s disease associated with Epstein- Barr virus infection. Am J Clin Pathol 84(3):385–390 32. Lee J-H, Kim Y, Choi J-W, Kim Y-S (2014) Prevalence and prognostic significance of Epstein-Barr virus infection in classical Hodgkin’s lymphoma: a meta- analysis. Arch Med Res 45(5):417–431 33. Hjalgrim H (2012) On the aetiology of Hodgkin lymphoma. Dan Med J 59(7):B4485 34. Razis DV, Diamond HD, Craver LF (1959) Hodgkin’s disease associated with other malignant tumors and certain non-neoplastic diseases. Am J Med Sci 238:327–335 35. Kharazmi E, Fallah M, Pukkala E et al (2015) Risk of familial classical Hodgkin lymphoma by relationship, histology, age, and sex: a joint study from five Nordic countries. Blood 126(17):1990–1995 36. Mack TM, Cozen W, Shibata DK et al (1995) Concordance for Hodgkin’s disease in identical twins suggesting genetic susceptibility to the young-adult form of the disease. N Engl J Med 332(7):413–418 37. Goldin LR, Pfeiffer RM, Gridley G et al (2004) Familial aggregation of Hodgkin lymphoma and related tumors. Cancer 100(9):1902–1908 38. Goldin LR, Björkholm M, Kristinsson SY, Turesson I, Landgren O (2009) Highly increased familial risks for specific lymphoma subtypes. Br J Haematol 146(1):91–94 39. Amiel JL, Terasaki P (1967) Study of leucocyte phenotypes in Hodgkin’s disease. In: Curtoni ES, Mattiuz PL, Tosi MR (eds) Histocompatibility testing. Munksgaaid, Copenhagen, pp 79–81 40. Hors J, Dausset J (1983) HLA and susceptibility to Hodgkin’s disease. Immunol Rev 70:167–192 41. Sud A, Thomsen H, Orlando G et al (2018) Genome- wide association study implicates immune dysfunction in the development of Hodgkin lymphoma. Blood 132(19):2040–2052 42. Urayama KY, Jarrett RF, Hjalgrim H et al (2012) Genome-wide association study of classical Hodgkin 1 Epidemiology of Hodgkin Lymphoma 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. lymphoma and Epstein-Barr virus status-defined subgroups. J Natl Cancer Inst 104(3):240–253 Delahaye-Sourdeix M, Urayama KY, Gaborieau V et al (2015) A novel risk locus at 6p21.3 for Epstein- Barr virus-positive Hodgkin lymphoma. Cancer Epidemiol Biomark Prev 24(12):1838–1843 Sud A, Thomsen H, Law PJ et al (2017) Genome- wide association study of classical Hodgkin lymphoma identifies key regulators of disease susceptibility. Nat Commun 8(1):1–11 Newell GR (1970) Etiology of multiple sclerosis and Hodgkin’s disease. Am J Epidemiol 91(2):119–122 Gutensohn N, Cole P (1977) Epidemiology of Hodgkin’s disease in the young. Int J Cancer 19:595–604 Gutensohn N, Cole P (1981) Childhood social environment and Hodgkin’s disease. N Engl J Med 304(3):135–140 Mack TM, Norman JE, Rappaport E, Cozen W (2015) Childhood determination of Hodgkin lymphoma among U.S. servicemen. Cancer Epidemiol Biomark Prev 24(11):1707–1715 Hjalgrim H, Ekström Smedby K, Rostgaard K et al (2007) Infectious mononucleosis, childhood social environment, and risk of Hodgkin lymphoma. Cancer Res 67(5):2382–2388 Glaser SL, Keegan THM, Clarke CA et al (2005) Exposure to childhood infections and risk of Epstein-Barr virus-defined Hodgkin’s lymphoma in women. Int J Cancer 115(4):599–605 Glaser SL, Clarke CA, Nugent RA, Stearns CB, Dorfman RF (2002) Social class and risk of Hodgkin’s disease in young-adult women in 1988– 94. Int J Cancer 98(1):110–117 Chang ET, Zheng T, Weir EG et al (2004) Childhood social environment and Hodgkin’s lymphoma: new findings from a population-based casecontrol study. Cancer Epidemiol Biomark Prev 13(8):1361–1370 Crump C, Sundquist K, Sieh W, Winkleby MA, Sundquist J (2012) Perinatal and family risk factors for Hodgkin lymphoma in childhood through young adulthood. Am J Epidemiol 176(12):1147–1158 Triebwasser C, Wang R, DeWan AT et al (2016) Birth weight and risk of paediatric Hodgkin lymphoma: findings from a population-based record linkage study in California. Eur J Cancer 69:19–27 Westergaard T, Melbye M, Pedersen JB et al (1997) Birth order, sibship size and risk of Hodgkin’s disease in children and young adults: a population- based study of 31 million person-years. Int J Cancer 72(6):977–981 Chang ET, Montgomery SM, Richiardi L et al (2004) Number of siblings and risk of Hodgkin’s lymphoma. Cancer Epidemiol Biomark Prev 13(7):1236–1243 Von Behren J, Spector LG, Mueller BA et al (2011) Birth order and risk of childhood cancer: a pooled analysis from five US states. Int J Cancer 128(11):2709–2716 21 58. Linabery AM, Erhardt EB, Fonstad RK et al (2014) Infectious, autoimmune and allergic diseases and risk of Hodgkin lymphoma in children and adolescents: a Children’s oncology group study. Int J Cancer 135(6):1454–1469 59. Isager H, Andersen E (1978) Pre-morbid factors in Hodgkin’s disease. I. Birth weight and growth pattern from 8 to 14 years of age. Scand J Haematol 21(3):250–255 60. Keegan THM, Glaser SL, Clarke CA et al (2006) Body size, physical activity, and risk of Hodgkin’s lymphoma in women. Cancer Epidemiol Biomark Prev 15(6):1095–1101 61. Larsson SC, Wolk A (2011) Body mass index and risk of non-Hodgkin’s and Hodgkin’s lymphoma: a meta-analysis of prospective studies. Eur J Cancer 47(16):2422–2430 62. Engeland A, Tretli S, Hansen S, Bjørge T (2007) Height and body mass index and risk of lymphohematopoietic malignancies in two million Norwegian men and women. Am J Epidemiol 165(1):44–52 63. Murphy F, Kroll ME, Pirie K et al (2013) Body size in relation to incidence of subtypes of haematological malignancy in the prospective million women study. Br J Cancer 108(11):2390–2398 64. Epstein MA, Achong BG, Barr YM (1964) Virus particles in cultured lymphoblasts from Burkitt’s lymphoma. Lancet 1:702–703 65. Henle G, Henle W, Diehl V (1968) Relation of Burkitt’s tumor-associated herpes-type virus to infectious mononucleosis. Proc Natl Acad Sci U S A 59(1):94–101 66. Odumade OA, Hogquist KA, Balfour HH (2011) Progress and problems in understanding and managing primary Epstein-Barr virus infections. Clin Microbiol Rev 24(1):193–209 67. Hjalgrim H, Askling J, Sørensen P et al (2000) Risk of Hodgkin’s disease and other cancers after infectious mononucleosis. J Natl Cancer Inst 92(18):1522–1528 68. Hjalgrim H, Askling J, Rostgaard K et al (2003) Characteristics of Hodgkin’s lymphoma after infectious mononucleosis. N Engl J Med 349(14):1324–1332 69. Alexander FE, Jarrett RF, Lawrence D et al (2000) Risk factors for Hodgkin’s disease by Epstein-Barr virus (EBV) status: prior infection by EBV and other agents. Br J Cancer 82(5):1117–1121 70. Alexander FE, Lawrence DJ, Freeland J et al (2003) An epidemiologic study of index and family infectious mononucleosis and adult Hodgkin’s disease (HD): evidence for a specific association with EBV +ve HD in young adults. Int J Cancer 107(2):298–302 71. IARC (1997) IARC monographs on the evaluation of carcinogenic risks to humans: tobacco smoke and involuntary smoking. IARC, Lyon, p 83 72. Coghill AE, Hildesheim A (2014) Epstein-Barr virus antibodies and the risk of associated malig- H. Hjalgrim and R. F. Jarrett 22 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. nancies: review of the literature. Am J Epidemiol 180(7):687–695 Mueller N, Evans A, Harris NL et al (1989) Hodgkin’s disease and Epstein-Barr virus. Altered antibody pattern before diagnosis. N Engl J Med 320(11):689–695 Levin LI, Chang ET, Ambinder RF et al (2012) Atypical prediagnosis Epstein-Barr virus serology restricted to EBV-positive Hodgkin lymphoma. Blood 120(18):3750–3755 Glaser SL, Lin RJ, Stewart SL et al (1997) Epstein- Barr virus-associated Hodgkin’s disease: epidemiologic characteristics in international data. Int J Cancer 70(4):375–382 Viruses JRF (2002) Hodgkin’s lymphoma. Ann Oncol 13(Suppl 1):23–29 Monnereau A, Orsi L, Troussard X et al (2007) History of infections and vaccinations and risk of lymphoid neoplasms: does influenza immunization reduce the risk? Leukemia 21(9):2075–2079 Montella M, Maso LD, Crispo A et al (2006) Do childhood diseases affect NHL and HL risk? A case- control study from northern and southern Italy. Leuk Res 30(8):917–922 Cozen W, Hamilton AS, Zhao P et al (2009) A protective role for early oral exposures in the etiology of young adult Hodgkin lymphoma. Blood 114(19):4014–4020 Engels EA, Hildesheim A (2018) Immunologic factors. In: Schottenfeld and Fraumeni cancer epidemiology and prevention. Oxford University Press, Oxford Frisch M, Biggar RJ, Engels EA et al (2001) Association of cancer with AIDS-related immunosuppression in adults. JAMA 285(13):1736 Shepherd L, Ryom L, Law M et al (2018) Differences in virological and immunological risk factors for non-Hodgkin and Hodgkin lymphoma. J Natl Cancer Inst 110(6):598–607 Grulich AE, Vajdic CM (2015) The epidemiology of cancers in human immunodeficiency virus infection and after organ transplantation. Semin Oncol 42(2):247–257 Landgren O, Caporaso NE (2007) New aspects in descriptive, etiologic, and molecular epidemiology of Hodgkin’s lymphoma. Hematol Oncol Clin North Am 21(5):825–840 Fallah M, Liu X, Ji J et al (2014) Hodgkin lymphoma after autoimmune diseases by age at diagnosis and histological subtype. J Eur Soc Med Oncol 25(7):1397–1404 Hemminki K, Försti A, Sundquist K, Sundquist J, Li X (2017) Familial associations of lymphoma and myeloma with autoimmune diseases. Blood Cancer J 7(1):e515–e515 Khankhanian P, Cozen W, Himmelstein DS et al (2016) Meta-analysis of genome-wide association studies reveals genetic overlap between Hodgkin lymphoma and multiple sclerosis. Int J Epidemiol 45(3):728–740 Montgomery S, Hajiebrahimi M, Burkill S et al (2016) Multiple sclerosis and risk of young-adult- 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103. onset Hodgkin lymphoma. Neurol Neuroimmunol Neuroinflamm 3(3):e227 Hjalgrim H, Rasmussen S, Rostgaard K et al (2004) Familial clustering of Hodgkin lymphoma and multiple sclerosis. J Natl Cancer Inst 96(10):780–784 Hollander P, Rostgaard K, Smedby KE et al (2015) Autoimmune and atopic disorders and risk of classical Hodgkin lymphoma. Am J Epidemiol 182(7):624–632 Martínez-Maza O, Moreno AD, Cozen W (2010) Epidemiological evidence: IgE, allergies, and hematopoietic malignancies. Cancer IgE 2010:79–136 Levin LI, Breen EC, Birmann BM et al (2017) Elevated serum levels of sCD30 and IL6 and detectable IL10 precede classical Hodgkin lymphoma diagnosis. Cancer Epidemiol Biomark Prev 26(7):1114–1123 Chang ET, Zheng T, Weir EG et al (2004) Aspirin and the risk of Hodgkin’s lymphoma in a population- based case-control study. J Natl Cancer Inst 96(4):305–315 Chang ET, Frøslev T, Sørensen HT, Pedersen L (2011) A nationwide study of aspirin, other non-steroidal anti-inflammatory drugs, and Hodgkin lymphoma risk in Denmark. Br J Cancer 105(11):1776–1782 Mondul AM, Weinstein SJ, Layne TM, Albanes D (2017) Vitamin D and cancer risk and mortality: state of the science, gaps, and challenges. Epidemiol Rev 39(1):28–48 Bowen EM, Pfeiffer RM, Linet MS et al (2016) Relationship between ambient ultraviolet radiation and Hodgkin lymphoma subtypes in the United States. Br J Cancer 114(7):826–831 van Leeuwen MT, Turner JJ, Falster MO et al (2013) Latitude gradients for lymphoid neoplasm subtypes in Australia support an association with ultraviolet radiation exposure. Int J Cancer 133(4):944–951 Monnereau A, Glaser SL, Schupp CW et al (2013) Exposure to UV radiation and risk of Hodgkin lymphoma: a pooled analysis. Blood 122(20):3492–3499 Sopori M (2002) Effects of cigarette smoke on the immune system. Nat Rev Immunol 2(May):372–377 Sergentanis TN, Kanavidis P, Michelakos T, Petridou ET (2013) Cigarette smoking and risk of lymphoma in adults. Eur J Cancer Prev 22(2):131–150 Castillo JJ, Dalia S, Shum H (2011) Meta-analysis of the association between cigarette smoking and incidence of Hodgkin’s lymphoma. J Clin Oncol 29(29):3900–3906 Kamper-Jørgensen M, Rostgaard K, Glaser SL et al (2013) Cigarette smoking and risk of Hodgkin lymphoma and its subtypes: a pooled analysis from the international lymphoma epidemiology consortium (InterLymph). Ann Oncol 24(9):2245–2255 Klatsky AL, Li Y, Baer D et al (2009) Alcohol consumption and risk of hematologic malignancies. Ann Epidemiol 19(10):746–753 1 Epidemiology of Hodgkin Lymphoma 104. Lim U, Morton LM, Subar AF et al (2007) Alcohol, smoking, and body size in relation to incident Hodgkin’s and non-Hodgkin’s lymphoma risk. Am J Epidemiol 166(6):697–708 105. Bernard SM, Cartwright RA, Darwin CM et al (1987) Hodgkin’s disease: case control epidemiological study in Yorkshire. Br J Cancer 55(1):85–90 106. Besson H, Brennan P, Becker N et al (2006) Tobacco smoking, alcohol drinking and Hodgkin’s lymphoma: a European multi-Centre case-control study (EPILYMPH). Br J Cancer 95(3):378–384 107. Monnereau A, Orsi L, Troussard X et al (2008) Cigarette smoking, alcohol drinking, and risk of lymphoid neoplasms: results of a French case- control study. Cancer Causes Control 19(10):1147–1160 108. Nieters A, Deeg E, Becker N (2006) Tobacco and alcohol consumption and risk of lymphoma: results of a population-based case-control study in Germany. Int J Cancer 118(2):422–430 109. Kanda J, Matsuo K, Inoue M et al (2010) Association of alcohol intake with the risk of malignant lym- 23 110. 111. 112. 113. 114. phoma and plasma cell myeloma in Japanese: a population-based cohort study (Japan public health center-based prospective study). Cancer Epidemiol Biomark Prev 19(2):429–434 Willett EV, O’Connor S, Smith AG, Roman E (2007) Does smoking or alcohol modify the risk of Epstein- Barr virus-positive or -negative Hodgkin lymphoma? Epidemiology 18(1):130–136 Gorini G, Stagnaro E, Fontana V et al (2007) Alcohol consumption and risk of Hodgkin’s lymphoma and multiple myeloma: a multicentre case-control study. Ann Oncol 18(1):143–148 Kroll ME, Murphy F, Pirie K et al (2012) Alcohol drinking, tobacco smoking and subtypes of haematological malignancy in the UK million women study. Br J Cancer 107(5):879–887 Psaltopoulou T, Sergentanis TN, Ntanasis- Stathopoulos I et al (2018) Alcohol consumption and risk of hematological malignancies: a meta-analysis of prospective studies. Int J Cancer 143(3):486–495 Stein RS, Morgan DS (2004) Hodgkin disease. In: Wintrobe’s clinical hematology. Lippincott Williams & Wilkins, Philadelphia, PA 2 The Role of Viruses in the Genesis of Hodgkin Lymphoma Ruth F. Jarrett, Henrik Hjalgrim, and Paul G. Murray Contents 2.1 Introduction 26 2.2 Hodgkin Lymphoma and Epstein-Barr Virus 2.2.1 E pstein-Barr Virus and the Pathogenesis of Hodgkin Lymphoma 2.2.2 Risk Factors for Epstein-Barr Virus-Associated Hodgkin Lymphoma 2.2.3 Epstein-Barr Virus and Hodgkin Lymphoma: A Causative Association? 2.2.4 Epstein-Barr Virus and the Clinicopathological Features of Hodgkin Lymphoma 26 27 29 32 2.3 Epstein-Barr Virus-Negative Hodgkin Lymphoma Cases 2.3.1 H odgkin Lymphoma and Herpesviruses Other Than Epstein-Barr Virus 2.3.2 Polyomaviruses and Hodgkin Lymphoma 2.3.3 Measles Virus and Hodgkin Lymphoma 2.3.4 The Virome, Anelloviruses, and Hodgkin Lymphoma 34 34 36 37 37 2.4 Conclusions 33 38 References 38 Abbreviations R. F. Jarrett (*) MRC-University of Glasgow Centre for Virus Research, Glasgow, UK e-mail: ruth.jarrett@glasgow.ac.uk BARTs H. Hjalgrim Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark cHL DDR1 EBER EBNA EBV HHV HL HLA HPyV HRS Department of Haematology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark e-mail: HHJ@ssi.dk P. G. Murray Bernal Institute, Limerick, Ireland Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK e-mail: Paul.Murray@ul.ie BHRF1 BamHI fragment A rightward transcripts BamHI-H rightward open reading frame 1 Classic Hodgkin lymphoma Discoidin domain receptor 1 EBV-encoded small RNAs EBV nuclear antigen Epstein-Barr virus Human herpesvirus Hodgkin lymphoma Human leukocyte antigen Human polyomavirus Hodgkin and Reed-Sternberg © Springer Nature Switzerland AG 2020 A. Engert, A. Younes (eds.), Hodgkin Lymphoma, Hematologic Malignancies, https://doi.org/10.1007/978-3-030-32482-7_2 25 R. F. Jarrett et al. 26 IHC LMP MCHL Immunohistochemistry Latent membrane protein Mixed cellularity Hodgkin lymphoma Merkel cell polyomavirus MicroRNAs Measles virus Nodular sclerosis Hodgkin lymphoma Open reading frame Polyomavirus Single nucleotide polymorphism Trichodysplasia spinulosa polyomavirus Torque teno midi virus Torque teno mini virus Torque teno virus 2.2 Hodgkin Lymphoma and Epstein-Barr Virus EBV is a herpesvirus with a worldwide distribution [10–13]. Over 90% of healthy adults are infected by EBV, and, following primary infection, the virus establishes a persistent infection with a reservoir in memory B-cells [14]. Although EBV is an extremely efficient transforming ORF agent, the virus is kept under tight control by cell- PyV mediated immune responses, and both primary SNP and persistent infections are usually asymptomTSPyV atic [10, 15]. EBV infection can be lytic or latent. Lytic TTMDV infection is associated with expression of a large TTMV number of viral genes, production of progeny TTV virus, and death of the infected cell; in contrast, latent infection is associated with expression of a small number of EBV genes, persistent infection, and growth transformation [10]. In B-cells trans2.1 Introduction formed by EBV in vitro, six EBV nuclear antigens (EBNA1, 2, 3A, 3B, 3C, and LP, also called Hodgkin lymphoma (HL) is a heterogeneous con- EBNA1–6) and three latent membrane proteins dition. Seminal papers published in 1957 and (LMP1, LMP2A, and LMP2B) are expressed 1966 suggested that HL in younger and older [10]. In addition, noncoding viral RNAs are tranadults had different etiologies and further sug- scribed in latently infected cells [16]. These gested an infectious etiology for young adult HL include two small non-polyadenylated tran[1, 2]. Subsequent epidemiological studies pro- scripts, the EBERs, and over 44 viral microRNAs vide broad support for these hypotheses [3, 4]. (miRNAs) located within introns of the BARTs Data linking young adult HL with a high standard (BamHI fragment A rightward transcripts) or of living in early childhood and lack of child-child around the coding region of the BHRF1 contact suggest that delayed exposure to common (BamHI-H rightward open reading frame 1) gene childhood infections may be involved in the etiol- [16–22]. Expression of the full set of latent genes ogy of these cases [5, 6]. There is now compelling is known as latency III [10, 13]. EBV gene evidence that a proportion of cases of HL are expression in EBV-positive lymphomas occurassociated with the Epstein-Barr virus (EBV). ring in the context of immunosuppression freParadoxically, older adult and childhood cases of quently follows this pattern, but more restricted HL are more likely to be EBV-associated than patterns of EBV gene expression are observed in young adult cases [7–9]. In this article, we review other malignancies, including cHL [10, 12, 13]. studies on viral involvement in HL with a focus The EBNA3 family proteins are immunodomion classic HL (cHL), since nodular lymphocyte- nant, and the other latent antigens elicit only subpredominant HL is considered a separate disease dominant or weak cell-mediated immune entity. The association with EBV will be dis- responses [23, 24]. The pattern of gene exprescussed with an emphasis on findings that support sion in EBV-associated malignancies most proba causal role for EBV in this malignancy. Studies ably depends on both the lineage and stage of investigating the direct involvement of other differentiation of the infected tumor cells and the exogenous viruses will be summarized. host EBV-specific immune response. MCPyV miRNAs MV NSHL 2 The Role of Viruses in the Genesis of Hodgkin Lymphoma In EBV-associated cHL (also referred to as EBV-positive cHL), all of the tumor cells, the Hodgkin and Reed-Sternberg (HRS) cells, are infected by EBV [25–27]. The EBV infection within tumors is also clonal suggesting that all of the tumor cells are derived from a single infected cell [28, 29]. The HRS cells express EBNA1, LMP1, LMP2A, and 2B, but the remaining EBNAs are downregulated (Fig. 2.1); the noncoding EBER RNAs and BART miRNAs are also expressed [25, 26, 30–33]. This pattern of gene expression is referred to as latency type II [10]. EBV infection of HRS cells can be readily demonstrated in sections of routinely fixed, paraffin-embedded material using either EBER in situ hybridization or LMP1 immunohistochemistry (IHC) (Fig. 2.1) [25, 26]. Reagents for both assays are commercially available. 2.2.1 27 35]. A pathognomonic feature of these cells is the global suppression of B-cell signature genes and inappropriate expression of genes associated with other hematopoietic lineages [36, 37]. Importantly, HRS cells do not express B-cell receptors (BCRs). Survival of germinal center B-cells normally requires signaling through both BCRs and CD40; HRS cells must, therefore, have acquired a nonphysiological survival mechanism(s). Functional studies of EBV, and LMP1 and LMP2A, support a role for the virus in HRS cell survival, transcriptional reprogramming, and immune evasion, as summarized below (Fig. 2.2). Epstein-Barr Virus and the Pathogenesis of Hodgkin Lymphoma The molecular pathogenesis of cHL and the origin of the HRS cell are described in detail in Chap. 3. Briefly, HRS cells have clonally rearranged immunoglobulin genes with evidence of somatic hypermutation, indicating a derivation from B-cells that have participated in a germinal center reaction [34, Fig. 2.2 EBV EBER in situ hybridization staining of EBV-positive Hodgkin and Reed-Sternberg cells. The characteristic staining pattern is observed in the nuclei of Hodgkin and Reed-Sternberg cells LMP2A LMP1 C-terminus activates signalling pathways e.g. NF-ĸB, JAK/STAT, PI3-K/Akt Induces chemokine/cytokine secretion that promotes tumour microenvironment Fig. 2.1 The latent membrane proteins of EBV contribute to the pathogenesis of classic Hodgkin lymphoma. Schematic diagram of LMP1 (left) and LMP2A (right) proteins in the cell membrane (gray bar). Both are transmembrane proteins that signal constitutively through the C-terminus in the case of LMP1 and the N-terminus in the LMP1 LMP2 N-terminus activates signalling pathways e.g. PI3-K/Akt Contributes to survival of BCR-negative B-cells case of LMP2A. The photomicrograph in the center shows the co-expression of LMP1 (red) and LMP2A (green) in the same Hodgkin and Reed-Sternberg cell in a tissue section of classic Hodgkin lymphoma. The nucleus of the Hodgkin and Reed-Sternberg cell stained blue with DAPI is arrowed 28 In 2005, three independent groups published data showing that germinal center B-cells lacking BCRs could survive and be immortalized by EBV [38–40]. In elegant experiments, Mancao and Hammerschmidt later showed that this survival function was dependent on LMP2A expression [41]. A series of in vivo and in vitro studies from the Longnecker laboratory further defined LMP2A function and showed that this viral protein could mimic an activated BCR and provide a survival signal to BCR-negative B-cells [42–44]. LMP2A expression in B-cells also results in downregulation of B-cell-specific genes and induction of genes associated with proliferation and inhibition of apoptosis, a gene expression profile similar to that seen in cHL-derived cell lines [45]. Constitutive activation of Notch1 by LMP2A, and subsequent inhibition of E2A and downregulation of EBF, two transcription factors that regulate B-cell development, appears to be involved in both survival signaling and transcriptional regulation [44]. Although these data suggest a role for LMP2A in the survival and reprogramming of HRS cells, many of the intracellular molecules involved in BCR signaling are downregulated in HRS cells, and therefore the precise contribution of LMP2A in cHL is not clear. CD40 signaling plays a critical role in the positive selection of germinal center B-cells expressing high-affinity immunoglobulin and their subsequent exit from the germinal center [46]. EBV LMP1 is an integral membrane protein which interacts with several signal transduction pathways to activate NF-κB, Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase [47–51]. In this way, LMP1 mimics a constitutively active CD40 molecule, although it provides a more potent and sustained signal. Many of the genes that are transcriptionally regulated by LMP1 in germinal center B-cells are also CD40 and NF-κB targets [52]. Activation of the NF-κB pathway, which is a feature of both EBV- positive and EBV-negative HRS cells, leads to upregulation of anti-apoptotic genes and is thought to play a key role in HRS cell survival [53–55]. LMP1 expression in germinal center B-cells also leads to increased expression of Id2, R. F. Jarrett et al. an inhibitor of the E2A transcription factor mentioned above, and repression of B-cell signature genes [52]; therefore, LMP1 may also contribute to transcriptional reprogramming. The EBV genome is maintained as an episome in infected cells; i.e., it does not normally integrate. The EBNA1 protein is responsible for maintenance of the genome in episomal form, genome replication, and genome partitioning during mitosis [10, 56]. EBNA1 can also influence both viral and cellular gene expression and appears to confer a B-cell survival advantage, although the impact of EBNA1 on oncogenesis in vivo is controversial [10, 57–60]. Interestingly, in the context of cHL, overexpression of EBNA1 in vitro leads to the appearance of multinucleated cells [57]. The EBV EBER RNAs are two small, non- polyadenylated RNA pol III transcripts that are stably expressed in the nuclei of all latently infected cells, including HRS cells. The precise function of the EBERs remains unclear, and, although not essential for transformation, expression of these small RNAs is required for efficient EBV-induced B-cell growth and transformation [16, 61–63]. EBV-encoded miRNAs were identified first in 2004, and their important role in EBV biology and oncogenesis is an area of intense study [16, 17, 22, 64, 65]. Functional analysis of the BHRF1 and BART miRNAs suggests roles in evading the immune response, promoting cell survival and proliferation, inhibiting viral reactivation, and fine-tuning gene expression [16, 22, 64, 65]. EBV-associated malignancies, including cHL, express BART miRNAs, but the BHRF1 miRNAs, which are associated with latency type III, are not expressed [33]. In vitro studies of knockout viruses lacking some or all of the miRNAs suggest that they have an important role in the initial stages of B-cell transformation by EBV; BHRF1 miRNAs play the predominant role with some contribution from BART miRNAs at low multiplicity of infection [22]. In contrast, in vivo studies in a murine huNSG model suggest that the main function of these miRNAs is to attenuate the antiviral T-cell-mediated immune response, leading to increased numbers of EBV- 2 The Role of Viruses in the Genesis of Hodgkin Lymphoma infected B-cells at later time points [66]. Again, these effects appear to be mediated by the BHRF1 miRNAs, as viruses deficient in only the BART miRNAs produced similar results to wild-type virus in this model system [66]. Ross et al. reported that miRNA BART11-5p downregulates the B-cell transcription factor EBF1, suggesting a plausible role for this miRNA in cHL [67]. EBV also regulates the expression of host miRNAs; infection of primary B-cells leads to a conspicuous downregulation of many miRNAs with the notable exception of mIR-155, which is highly expressed by both EBV-positive and EBV- negative HRS cells [68, 69]. Analysis of host miRNAs in cHL is described in more detail in Chap. 4, but it has been reported that EBV status of tumors is associated with differences in expression pattern [70]. While most studies have investigated the effects of the latent genes in isolation, there is evidence that co-expression of the EBV latent genes is important. For example, it has been shown that LMP1 is transforming when expressed alone in transgenic mouse B-cells [71]. However, when LMP2A is expressed together with LMP1, the resulting mouse B-cells are normal [71]. Comparison of LMP1 and LMP2A in B-cells confirms they have both synergistic and counteracting transcriptional effects [72]. Furthermore, in another study it was shown that LMP1 and LMP2A co-expression in mouse B-cells resulted in tumors, but only if the animals were immunosuppressed suggesting that the combined expression of these latent genes is immunogenic in vivo [73]. There is evidence that the tumor microenvironment in EBV-positive and EBV-negative cHL is different. Thus, the T-helper cells present in EBV-positive cHL are enriched for functional Th1 cells [74]. EBV-positive cHL is also preferentially infiltrated by regulatory Type 1 cells (Tr1), which express ITGA2, ITGB2, and LAG3 and secrete IL-10 [75]. This Th1-biased infiltrate is consistent with previous reports of higher numbers of activated CD8+ T-cells in EBVpositive cHL [76] and is also associated with the presence of predominantly M1-polarized macrophages [77]. There is evidence that the EBV 29 latent genes are responsible, at least in part, for the recruitment and modification of this tumor microenvironment. LMP1, in particular, has been shown to induce expression of many of the chemokines and cytokines secreted by EBV-infected HRS cells [78, 79]. The cHL tumor microenvironment also contributes to the suppression of host anti- EBV- specific immunity. Thus, while LMP1 and LMP2A proteins are targets of CD8+ cytotoxic T lymphocytes, it is clear that immune effectors present in the tumor tissues of EBVpositive cHL cannot kill the virus-infected cells [80, 81]. LMP1 probably also contributes to the suppression of EBV-specific immunity through its ability to induce expression of the immunosuppressive cytokines, including IL-10, and upregulate the immune checkpoint ligand, PD-L1 [82, 83]. LMP1 also upregulates the collagen receptor, discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase expressed by HRS cells [84]. Engagement of DDR1 by collagen leads to the increased survival of lymphoma cells, thus providing a link between the expression of LMP1 and pro-survival signaling from the tumor microenvironment. 2.2.2 isk Factors for Epstein-Barr R Virus-Associated Hodgkin Lymphoma It is clear that EBV is associated with only a proportion of cHL cases. In industrialized countries around one third of cases are EBV-associated, whereas in Africa and Central and South America, this proportion is significantly higher [8, 9, 85, 86]. EBV-associated cHL cases are not randomly distributed among all cHL cases, and the demographic features and risk factors for the development of EBV-positive and EBV-negative cHL show distinctive features [8, 9, 86]. Childhood (<10 years) and older adult (50+ years) cases are more likely to be EBV-associated than young adult cases (15–34 years) [7, 8, 86]. Among EBV-associated cases, males outnumber females by approximately 2:1, whereas males and females are more evenly represented among EBV-negative cases [9, 86]. In developing countries, childhood cHL is more com- R. F. Jarrett et al. 30 mon than in industrialized countries, resulting in a higher proportion of EBV-associated cases [9, 86, 87]. Material deprivation is associated with an increased proportion of EBV-positive childhood cHL cases in industrialized countries, and there is some evidence that this also holds for older adult cases [85, 88]. EBV infection usually occurs in childhood, and in many parts of the world, there is almost universal infection by the age of 5 years [11, 89]. If infection is delayed until adolescence, as is increasingly observed in industrialized countries, primary EBV infection manifests as infectious mononucleosis in around 25% of individuals [90]. Infectious mononucleosis has been associated with an increased risk of EBV-associated cHL in some, although not all, studies [6, 91–93]. The increased risk appears relatively short-lived with a median time interval between infectious mononucleosis and cHL of approximately 3–4 years (see Chap. 1: Epidemiology of Hodgkin Lymphoma) [92, 93]. Thus, in both developing and developed countries, there appears to be a period following primary EBV infection, probably lasting several years, in which risk of EBV- associated cHL is increased. cHL occurring in the context of immunosuppression is almost always EBV-associated (see Chap. 1: Epidemiology of Hodgkin Lymphoma) [94, 95], and it is likely that the increased incidence of EBV-associated cHL that occurs in older adults is related to immune senescence. Based on these data, we have proposed an extension of MacMahon’s model of HL that divides cHL into four subgroups on the basis of tumor EBV status, age at diagnosis, and age at infection by EBV (Fig. 2.3) [2, 96]. Recent data also suggest that humoral and cell-mediated responses to EBV modulate risk of EBV-associated cHL. Levin and colleagues examined anti-EBV antibody profiles in serum samples from military personnel (mainly young men) that had been collected several years before the diagnosis of cHL [97]. Individuals who subsequently developed EBV-positive, but not EBV- negative, cHL were more likely to have elevated Incidence 4 3 1 2 10 25 50 Age (years) Fig. 2.3 The four-disease model of classic Hodgkin lymphoma. This model divides classic Hodgkin lymphoma into four subgroups based on EBV tumor status, age at diagnosis, and age at EBV infection. Three groups of EBV-associated disease are recognized: (1) a childhood disease, usually occurring below the age of 10 years, which is commoner in developing countries; (2) a disease, most commonly seen in young adults, which occurs following infectious mononucleosis; and (3) a disease associated with poor control of EBV infection, which is typified by the older adult cases but can occur at other ages, particularly in the context of immunosuppression. (4) Superimposed on these is a single group of EBV- negative classic Hodgkin lymphoma cases, which account for the young adult age-specific incidence peak seen in industrialized countries. The relative incidence of each of these four disease subgroups will determine the overall shape of the age-specific incidence curve in any geographical locale 2 The Role of Viruses in the Genesis of Hodgkin Lymphoma antibody titers to EBV viral capsid and early antigens and an anti-EBNA-1/anti-EBNA2 antibody ratio ≤1.0 when compared to controls. Decreased anti-EBNA-1/anti-EBNA2 antibody ratios have been previously associated with EBV-associated cHL [98], and it has been suggested that a ratio ≤ 1.0, which persists for more than 2 years after infectious mononucleosis, indicates defective control of persistent EBV infection [99]. Variations in EBNA-1 titer are significantly associated with polymorphisms in the human leukocyte antigen (HLA) region [100], suggesting that titers may, in part, be genetically determined and relate to the findings described below. Data from HLA association studies and genome-wide association studies (GWAS) show clear associations between cHL risk and both HLA alleles and single nucleotide polymorphisms (SNPs) in this region. Although some SNPs appear to be associated with all cHL, independent of EBV status, most HLA associations differ between EBV-positive and EBV-negative subgroups [101–108]. Both HLA class I and II alleles are associated with EBV-positive cHL, whereas EBV-negative cHL is largely associated with class II alleles [102, 103, 105, 107]. Since class I and II alleles present peptides from 31 pathogens to CD8- and CD4-positive T-cells, respectively, this suggests that genetically determined differences in the cell-mediated response to EBV influence disease risk. HLA-A∗01 is associated with an increased risk of EBVassociated cHL, whereas HLA-A∗02, specifically A∗02:01, is associated with decreased risk [102, 103]. Associations with these alleles are independent, i.e., the increased risk associated with A∗01 is not simply due to lack of A∗02, and effects are dependent on the copy number of each of the alleles [103] (Fig. 2.4). As a result, there is an almost tenfold variation in odds of EBV- associated cHL between HLA-A∗01 homozygotes and HLA-A∗02 homozygotes [103]. More recent data suggest that B∗37:01 is also associated with an increased risk of EBVpositive cHL [105, 107]. Class II alleles have been less extensively studied, but Huang et al. reported an increased frequency of DR10 alleles in patients with EBV-positive cHL compared to controls, and we have detected protective effects of DRB1∗15:01 and DPB1∗01:01 [105, 107]. In addition, the SNP rs6457715, which is located close to the HLA-DPB1 gene, is strongly associated with EBV-positive but not EBV-negative cHL [108]. Sex Age group A*01:01 add A*02:01 add IM A*02:01 x IM interaction 0 2 4 6 8 Odds Ratio Fig. 2.4 Risk factors for EBV-associated classic Hodgkin lymphoma in adults. Forest plot showing odds ratios and 95% confidence intervals for development of EBVassociated Hodgkin lymphoma from a case series analysis of HLA and non-HLA risk factors [103]. Increased risk is associated with male sex, older age (age ≥50 years versus 15–34 years), possession of HLA-A∗01:01 alleles (add, additive effect), and prior history of infectious mononucleosis (IM). Possession of HLA-A∗02:01 alleles is associated with decreased risk, and abrogation of the increased risk associated with IM R. F. Jarrett et al. 32 Cytotoxic T-cell responses, restricted through HLA class I, are critical for the control of EBV infection, and A∗02 is known to present a wide range of peptides derived from EBV lytic and latent antigens, including those expressed by HRS cells [23, 24]. In contrast, there are no well-characterized A∗01-restricted EBV epitopes [24], and EBV-specific T-cell responses restricted through A∗01:01 have not been described [109]. The observed associations with HLA-A, therefore, seem biologically plausible. However, HLA-A∗01 is in strong linkage disequilibrium with HLA-B∗08, which is associated with immunodominant EBV-specific cytotoxic T-cell responses, and yet there is no protective effect associated with this allele [107]. The biological basis underlying associations between HLA alleles and EBV-associated cHL is therefore not clear. Further work is also necessary to determine whether the critical HLA-A-restricted cell- mediated immune responses are directed toward EBV-infected HRS cells or whether it is the control of persistent EBV infection, i.e., the host-virus equilibrium, which is all-important. The increased risk associated with individual class I alleles favors the idea that failure to respond to a particular protein, or very restricted group of proteins, determines risk; this focusses attention on EBV proteins expressed by HRS cells. Consistent with this, no EBNA1, LMP1, or LMP2 epitopes restricted by B∗37:01 have been identified although a B∗37:01-restricted EBNA3C epitope has been described [24]. As mentioned above, prior infectious mononucleosis has been associated with an increased risk of EBV-positive cHL [91–93, 110]. Infectious mononucleosis has also been associated with the same genotypic markers (microsatellites and SNPs) in the HLA class I region as EBV-positive cHL, albeit with lesser statistical significance [111]. These data raised the possibility that the association between infectious mononucleosis and EBV-associated cHL resulted from shared genetic susceptibility. However, HLA-A typing of over 700 cHL cases with available self-reported history of infectious mononucleosis revealed that prior infectious mononucleosis was independently associated with EBV-associated cHL after adjusting for the effects of HLA-A alleles [103]. In addition, a statistically significant interaction between prior infectious mononucleosis and HLA-A∗02 was detected; the effect of this was to abrogate the increased risk of EBV-associated cHL following infectious mononucleosis in HLA-A∗02positive individuals [103]. These results suggest that the increased risk of EBV-associated cHL following infectious mononucleosis is modified by the EBV-specific cytotoxic T-cell response restricted through HLA-A∗02. Thus, it is possible that different HLA alleles exert their effects at different stages in the natural history of EBVassociated cHL. Associations with childhood cHL and infectious mononucleosis suggest that there is a window of time following primary EBV infection when there is an increased risk of EBVassociated cHL and that genetic factors, specifically HLA-A genotype, modify this risk. EBV-associated cHL patients have higher numbers of EBV-infected cells than patients with EBV-negative disease [112], and infectious mononucleosis patients have very high numbers of circulating EBV- infected B-cells, which decrease over time [113]. The number of EBVinfected cells carried by an individual is therefore likely to influence the risk of EBV-associated cHL. It may, therefore, be possible to decrease the risk of EBV-positive cHL by EBV vaccination, even in the absence of sterilizing immunity [114], or by treatment of infectious mononucleosis with antiviral agents. 2.2.3 Epstein-Barr Virus and Hodgkin Lymphoma: A Causative Association? In the absence of good animal models and the ability to prevent EBV infection, it is difficult to prove that the association between EBV and cHL is causal; however, consideration of the viral, molecular, and epidemiological data pro- 2 The Role of Viruses in the Genesis of Hodgkin Lymphoma vides support for this idea. (1) The EBV infection in EBV-positive cHL tumors is clonal indicating that all the tumor cells are derived from a single EBV-infected cell. (2) In EBVassociated cases, all HRS cells are infected by the virus. Although EBNA1 facilitates both synchronous replication of the viral episome with cellular DNA and genome partitioning, this process is not 100% efficient [56]. If the virus were not required for maintenance of the transformed phenotype, a gradual loss of viral genomes from the tumor cells would be anticipated. (3) EBV is present in the tumor cells of a significant proportion of cHL cases. Although most adults are infected by EBV, only 1–50 per million B-cells are EBV-infected in healthy individuals [115]. If EBV were simply a passenger virus, i.e., present in a B-cell that was subsequently transformed by other mechanisms, EBV-associated cHL would be a rare occurrence. (4) LMP1 and LMP2A have plausible biological functions in the pathogenesis of cHL, as described above. (5) Crippling mutations of immunoglobulin genes have been described in a quarter of cHL cases, and almost all of these cases are EBV-associated [116]. This is consistent with the idea that EBV rescues HRS cells (or precursors) that have destructive mutations of their immunoglobulin genes from apoptosis. (6) Recent studies show that EBV-positive cHL has significantly fewer cellular mutations, including chromosomal breakpoints and aneuploid autosomes than EBV- negative cHL [117, 118]. Deleterious mutations of the TNFAIP3 and NFKBIA genes, which are both negative regulators of NF-κB signaling, are also much more frequent in HRS cells from EBV-negative cases (see Chap. 3) [119–123]. (7) EBV-associated cHL cases share genetic risk factors for disease development, which are generally distinct from those associated with EBV-negative cHL [101–105, 107, 108, 124, 125]. (8) In some cases, the development of EBV-associated cHL is temporally related to primary EBV infection [92, 93, 95]. (9) Individuals who subsequently develop EBVassociated cHL have abnormal EBV antibody profiles before diagnosis [97]. 2.2.4 33 Epstein-Barr Virus and the Clinicopathological Features of Hodgkin Lymphoma Although the above data indicate that EBV- positive and EBV-negative cHL have distinct natural histories, the phenotypic expression of both processes appears remarkably similar. Gene expression profiling of HRS cells suggests that EBV has only a small influence on the transcription profile of established HRS cells [126]. However, EBV status does show clear associations with histological subtype. In a meta-analysis of published studies of EBV and cHL, Lee et al. reported that 66% of MCHL cases are EBV- associated, compared to 29% of NSHL cases [86]. Despite this difference, it is clear that “barn door” NSHL cases can be EBV-positive, and so the lack of a complete correlation between histological subtype and EBV status is not simply due to the criteria used in, and subjective nature of, histological subtyping. In industrialized countries, NSHL is much more common than MCHL, and in our experience, the majority (just) of EBV- positive cases in the UK are, in fact, NSHL and not MCHL. Early studies investigating clinical outcome in relation to EBV status in cHL appeared conflicting, and the meta-analysis performed by Lee et al., which was not able to stratify patients by age, did not find any associations with survival. However, a consistent picture has emerged from populationbased studies with age stratification of patients [127–130]. In young adult patients, there appears to be no significant difference in overall survival by EBV status. In contrast, EBV positivity is associated with inferior outcome among patients aged 50 years and over. It is not clear whether this difference is related to the disease process itself or whether it reflects an underlying comorbidity or immune dysregulation that potentially predisposes to EBV-associated cHL. EBV status is not routinely used in therapeutic decisions, but it is possible that this group of patients would benefit from alternative treatments, such as third-party cytotoxic lymphocyte infusions or novel therapies tar- R. F. Jarrett et al. 34 geting EBV. Biomarker levels may also vary by EBV status; for instance, CCL17 (TARC) levels are lower in patients with EBV-associated cHL, but monitoring of plasma EBV levels (a form of circulating tumor DNA) can be used to assess treatment response and detect relapse in these patients [131, 132]. Further studies investigating these issues are required. 2.3 Epstein-Barr Virus-Negative Hodgkin Lymphoma Cases Adolescent and young adult cHL cases are the group least likely to be associated with EBV, and yet it is for these cases that there is most epidemiological evidence suggesting viral involvement. Early studies reported consistent associations between young adult HL and correlates of a high standard of living in early childhood [133]. Many of these associations with social class variables have not been detected in recent studies, most probably reflecting societal changes; however, an increased risk of young adult HL in individuals with less than 1 year of preschool attendance has been observed [6, 93]. Collectively, the data suggest that diminished social contact in early childhood is associated with an increased risk of this disease. Interview and questionnaire data generally support the idea that young adult HL patients have experienced fewer common infections in childhood [91, 134]. This has led to speculation that young adult HL is associated with delayed exposure to one or more common childhood infections. A frequent suggestion is that EBV is involved in all cases of cHL but uses a hit-and-run mechanism in “EBV-negative” cases. This possibility is very difficult to exclude, but the available data indicate that it cannot account for all “EBV- negative” cases. Importantly, not all cases are EBV-infected [98, 135]; in fact, we found that EBV-negative cHL cases in the 15- to 24-year age group were more likely to be EBV- seronegative than age-matched controls [135]. Also, there is no evidence for integration of incomplete EBV genomes in “EBV-negative” cHL biopsies [135, 136]. Alternative hypotheses are that lack of exposure to pathogens in early life shapes the microbiome and immune defenses, leading to an increased risk of developing cHL in young adulthood [137], or that EBV-negative cHL is associated with delayed exposure to another common virus that is directly involved in disease pathogenesis. Candidate viruses that are common and have transforming potential include herpesviruses and polyomaviruses. Any virus with a direct transforming role would be expected to be present in all HRS cells within tumors. 2.3.1 Hodgkin Lymphoma and Herpesviruses Other Than Epstein-Barr Virus At present, there are nine known human herpesviruses (HHVs), including EBV (officially HHV- 4). All are widespread in distribution, except herpes simplex virus 2 (HHV-2) and HHV-8. EBV and Kaposi sarcoma herpesvirus (KSHV, officially HHV-8) belong to the gammaherpesvirus subfamily of herpesviruses; both infect lymphoid cells and are tumor viruses. KSHV causes Kaposi sarcoma and rare forms of lymphoma but is not associated with cHL [138–141]. There is also no evidence of involvement of the alpha- herpesviruses, herpes simplex virus 1, and varicella zoster virus [140]. In contrast, genomes of the betaherpesviruses, human cytomegalovirus, HHV-6A, HHV-6B, and HHV-7, have been detected in cHL tumors using sensitive molecular assays. Schmidt et al. detected human cytomegalovirus genomes by PCR in 8/86 HL biopsies [139], although smaller case series failed to identify this virus in tumor samples [140, 142–144]. HHV-7 has been detected in 20–68% of HL biopsies by PCR [139, 140, 144, 145]. However, negative results were obtained using Southern blot analysis, which is much less sensitive than PCR but would be expected to detect a virus present in all HRS cells [146], and there is no evidence that the virus is present in HRS cells [145]. There is, 2 The Role of Viruses in the Genesis of Hodgkin Lymphoma therefore, no evidence for direct involvement of HHV-7 in cHL pathogenesis. HHV-6 deserves special mention because this lymphotropic virus has been consistently linked with cHL. HHV-6 is now classified as two distinct viruses, HHV-6A and HHV-6B [147], rather than two variants, but until recently many studies have not distinguished between the two viruses. Serological studies have shown that HHV-6 antibody titers and, in some studies, seroprevalence are higher in HL cases than controls [148–150]. We also found that young adults with non-EBV- associated HL had higher titers of HHV-6 antibodies than age-matched cases with EBV-associated disease (unpublished results). HHV-7 antibody titers were similar in the two groups of cases suggesting a specific association between HHV-6 and cHL. HHV-6 genomes have been consistently detected in HL biopsies using PCR although detection rates range from 8% to 79% [139, 140, 144, 150–155], and some studies have reported similar detection rates in reactive lymph nodes [144, 152]. Differences in PCR assay sensitivity and the amount of DNA assayed most probably account for the differences in detection rate since viral genome copy numbers within biopsies are often low. Up to 87% of NSHL cases have been reported to be HHV-6-positive [155, 156], but it is clear that these PCR-positive cases include both EBV-associated and EBV-non-associated cases [140, 152, 155, 156]. Both HHV-6A and B have been detected within biopsies with four studies showing a clear bias toward HHV-6B [140, 151, 152, 155], one detecting a higher proportion of HHV-6A-positive tumors [139], and one detecting HHV-6A and B as well as dual infections [156]. The low viral genome copy in many tumors suggests that the virus cannot be present in every HRS cell and raises the suspicion that the virus is in cells in the reactive component of tumors. Very high viral copy numbers must also be interpreted with caution since inherited chromosomally integrated HHV-6 (iciHHV-6) is transmitted in the germline in around 1% of individuals and gives rise to high viral loads since viral genomes are present in every nucleated cell 35 in the body [157–159]. Following exclusion of cases with iciHHV-6, studies using the less sensitive technique of Southern blot analysis have largely been negative suggesting a low viral copy number within tumors [138, 150, 152, 153, 160]. In contrast, in EBV-associated cHL, EBV genomes are almost always detectable using this technique [7, 20, 128]. The critical question is whether HHV-6 infects HRS cells and, if so, is the virus present in every HRS cell. Early studies using in situ hybridization and IHC reported that the virus was present in cells in the tumor microenvironment, either exclusively [152, 161] or with occasional positive HRS cells [162, 163]. However, two recent studies described HHV-6-positive HRS cells [156, 164], and we detected HHV-6 transcripts in an RNAseq analysis of HRS cells enriched from an EBV-negative cHL biopsy (unpublished data), thus renewing interest in cHL and HHV-6. Lacroix et al. made a polyclonal antiserum to the DR7 open reading frame (ORF) of HHV-6B (designated DR7B) to examine the cellular localization of the virus in PCR-positive cases [164]. They selected this particular ORF because the equivalent HHV-6A ORF has transforming properties and the translated protein binds p53 and inhibits p53-activated transcription [153, 165]. It is likely that the DR7 ORF is expressed as the second exon of DR6, a larger nuclear protein [166, 167]. Using this antiserum, cytoplasmic staining of HRS cells was identified in 28/38 PCR-positive biopsies [164]. In 17 cases, positive staining was exclusive to HRS cells, and in further 17 cases, positive staining of cells in the microenvironment was noted. In 15 of the 38 biopsies, HRS cells were also positively stained using an antibody to the HHV-6 gp116/64/54 glycoprotein. Further analyses suggested that DR7B bound p53, upregulated NF-κB p105 and p65 promoters, significantly increased NF-κB activation, and induced upregulation of Id2. In the second study, Siddon et al. investigated biopsies from 21 NSHL cases, including 18 that were HHV-6-positive by PCR, using multiple approaches [156]. In ten cases, staining of HRS cells was demonstrated using a commercially available monoclonal antibody raised R. F. Jarrett et al. 36 against virus lysate (Santa Cruz Biotechnology); scattered positive HRS cells were also demonstrated using antibodies to the late viral proteins p41 and p98. Laser capture microdissection coupled with PCR confirmed the presence of HHV-6 DNA in pooled HRS cells from eight of the ten IHC-positive biopsies. This study provides the most convincing evidence to date that HHV-6 can infect HRS cells but does not show that the virus is present in every HRS cell. Furthermore, the IHC staining pattern suggests lytic replication (or abortive replication) rather than latent infection, and so the outcome of viral infection in these cells is not clear. As mentioned above, some individuals inherit HHV-6 in the germline [157, 159]. The first study to demonstrate chromosomally integrated HHV-6 investigated three patients with high viral loads in peripheral blood, including one with cHL [168, 169]. To determine whether iciHHV-6 is associated with cHL, we examined 936 cHL cases and 563 controls but found no evidence that iciHHV-6 was overrepresented among cases [170]. Overall, the data do not support the idea that HHV-6 has a direct role in disease pathogenesis. However, it is possible that HHV-6 is frequently reactivated in cHL tumors. CD134 is the cellular receptor for HHV-6B [171], and it is possible that CD134-positive T-cells in the cHL microenvironment [74] facilitate replication of HHV-6B. Robust in situ hybridization assays for HHV-6 are required to confidently rule out a direct role in cHL. To search for novel members of the herpesvirus family, we and others have designed degenerate PCR assays which amplify herpesvirus polymerase and glycoprotein B gene sequences [140, 172]. The primer sequences in degenerate assays are derived from well-conserved peptide motifs in amino acid sequences of proteins; therefore, these assays should have the ability to detect genomes from known and currently unknown viruses [173]. Using herpesvirus polymerase assays, we have not detected novel herpesviruses in cHL biopsies although the assays had sufficient sensitivity to detect EBV in EBV- associated cases, as well as low-level HHV-6 and HHV-7 infection [140] (and unpublished results). 2.3.2 Polyomaviruses and Hodgkin Lymphoma There are now (at least) 14 human polyomaviruses (HPyVs) [174–178]. JCV and BKV were discovered over 40 years ago, but the others have all been discovered since 2007 with the advent of modern molecular techniques for virus discovery. Seroprevalence studies suggest that the majority of adults are infected by BKPyV, KIPyV, WUPyV, MCPyV, HPyV6 and 7, and TSPyV and a significant minority by JCPyV, HPyV9, and HPyV12 [176, 179–181]. Among this expanding list of HPyVs, only JCPyV, BKPyV, TSPyV (associated with trichodysplasia spinulosa in immunosuppressed persons), and MCPyV show clear disease associations. MCPyV is associated with Merkel cell carcinoma and has been categorized by IARC as a group2A carcinogen (probably carcinogenic to humans) [175, 182, 183]. It is the only HPyV to be unambiguously linked with a specific malignancy; however, other polyomaviruses have oncogenic potential. Several laboratories have looked for evidence of HPyV genomes in cHL biopsies. Using sensitive quantitative PCR assays, we found no evidence of JCV or BKV genomes in 35 cHL biopsies [184]. Hernandez-Losa et al. detected JCV in 1/20 and BKV in 2/20 cHL samples using a multiplex, nested PCR [144]. Robles et al. reported that MCPyV seroprevalence was slightly higher in HL cases than controls, 84.4% compared to 81.2%, but differences were not statistically significant [185]. Two quantitative PCR studies detected MCPyV genomes in a small proportion (1/30 and 3/41) of cHL tumors [186, 187]; viral copy numbers were low making it extremely unlikely that this virus is playing any role in disease pathogenesis. To date, there have been no reports on the prevalence of the more recently identified viruses in cHL. 2 The Role of Viruses in the Genesis of Hodgkin Lymphoma Degenerate PCR assays have also been applied to the study of PyVs and HL [184, 187]. Volter et al. examined five cases of HL using a degenerate PCR assay based on the viral VP1 protein but did not detect any evidence of polyomavirus infection [187]. We examined 35 cases of cHL, including 23 EBV-negative cases, using 3 degenerate PyV assays based on the large T antigen, and also obtained negative results [184]. The latter assays were designed before 2006 and therefore before most HPyVs were discovered. Alignment of large T antigen amino acid sequences from the recently identified viruses suggests that our assays would be able to detect KIPyV, WUPyV, TSPyV, and HPyV9 and 10 but not MCPyV, HPyV6, and HPyV7; however, given the tropism of the latter viruses for skin, it is unlikely that they are involved in cHL [176]. Overall, these results provide no evidence for HPyV involvement in the pathogenesis of cHL, but it remains possible that an unknown HPyV has escaped detection. 2.3.3 Measles Virus and Hodgkin Lymphoma In 2003, Benharroch and colleagues reported an association between measles virus (MV) and cHL [188]. They subsequently reported that MV proteins were detectable by IHC in HRS cells from most HL cases [189]. MV RNA was also detected by RT-PCR and in situ hybridization in a significant minority of the cases examined [189]. Subsequent studies have failed to confirm these associations [190, 191]. Our group found no evidence of MV in 97 cHL cases examined by IHC and 20 cHL cases investigated using RT-PCR [191]. Similarly, Maggio et al. found no evidence of MV genomes or transcripts in HRS cells microdissected from biopsies from 18 German and 17 Israeli HL cases [190]; the latter cases had previously scored positive for MV antigens [190]. Epidemiological studies have also failed to show that MV infection is a risk factor for the development of cHL; on the contrary, the data suggest a mild protective effect of prior MV infection [91, 134, 192]. 2.3.4 37 The Virome, Anelloviruses, and Hodgkin Lymphoma It is now recognized that the microbiome, which is thought to play an important role in shaping the immune system, includes a large number of viral species (the virome). Anelloviruses account for around 70% of these viruses [193]. The anellovirus family includes a large number of genetically diverse viruses with small, circular, single-stranded DNA genomes, which are classified in the Torque teno virus (TTV), Torque teno midi virus (TTMDV), and Torque teno mini virus (TTMV) genera in humans. They are widely distributed, acquired early in life, and establish persistent infections, but have not yet been associated with any disease; however, it has been suggested that they can modulate both innate and adaptive immune responses [194]. In 2004, Jelcic et al. reported the isolation of 24 novel TTVs from a spleen of an HL patient [195]. This led zur Hausen and de Villiers to suggest that TTVs could play a role in the development of leukemias and lymphomas that are associated with a “protected childhood environment” [196]. In their model, they postulated that TTVs and related anelloviruses increase the risk of chromosomal abnormalities and that anellovirus load is increased in individuals who have experienced fewer infections [196]. Increased TTV loads could also contribute to cHL through modulation of immune defenses. TTVs have also been identified in cHL tumor biopsies by other groups [197, 198], but these studies detected TTVs at a similar frequency in other lymphomas [197] and reactive nodes [198]. In a recent metagenomic analysis, Pan et al. analyzed the virome in blood samples from 19 HL patients, 252 nonHodgkin lymphoma patients, and 40 healthy controls from China [199]. Eleven novel, but closely related, TTMVs were identified in three of the HL patients but not in the other patients or controls. The significance of these findings is currently unclear. Further investigation of the virome in both cHL patients and individuals with lack of social contact in early childhood is required to understand the potential contribution of anelloviruses, the virome, and the microbiome to the risk of cHL. R. F. Jarrett et al. 38 2.4 Conclusions 5. While the evidence suggesting a causal relationship between EBV and a proportion of cHL cases appears strong, current data do not show a consistent and specific association between any virus and EBV-negative cHL. This does not exclude viral involvement since the difficulty of obtaining large numbers of highly enriched HRS cells has precluded the use of certain techniques, such as representational difference analysis, in the analysis of cHL [137]. Next-generation sequencing methods have opened new avenues for virus discovery and have led to the identification of numerous novel viruses in the last few years [139, 140, 156]. These techniques provide our best hope of discovering a new virus in EBV- negative HRS cells. It is possible that cellular mutations substitute for the functions of EBV genes in EBV-negative HRS cells [126]. Deleterious mutations of inhibitors of the NF-κB pathway, including genes encoding A20 and IκBα, appear to be present in the HRS cells of many cases of EBV-negative cHL (see Chap. 3) [90–94], and it is possible that these mutations substitute for LMP1. However, there is no obvious link between these mutations and the epidemiological features of cHL, and involvement of another virus(es) with either a direct or indirect role still appears attractive. Understanding the role of viruses in EBV-negative cHL could potentially open up possibilities for disease prevention as well as novel therapeutic targets and is a goal worth pursuing. 17. References 18. 1. MacMahon B (1957) Epidemiological evidence of the nature of Hodgkin's disease. Cancer 10:1045–1054 2. MacMahon B (1966) Epidemiology of Hodgkin's disease. Cancer Res 26:1189–1201 3. Gutensohn NM (1982) Social class and age at diagnosis of Hodgkin’s disease: new epidemiologic evidence for the “two-disease hypothesis”. Cancer Treat Rep 66:689–695 4. Alexander FE, McKinney PA, Williams J, Ricketts TJ, Cartwright RA (1991) Epidemiological evidence 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 19. 20. 21. for the ‘two-disease hypothesis’ in Hodgkin's disease. Int J Epidemiol 20:354–361 Gutensohn NM, Shapiro DS (1982) Social class risk factors among children with Hodgkin’s disease. Int J Cancer 30:433–435 Chang ET, Zheng T, Weir EG et al (2004) Childhood social environment and Hodgkin’s lymphoma: new findings from a population-based case-control study. Cancer Epidemiol Biomark Prev 13:1361–1370 Jarrett RF, Gallagher A, Jones DB et al (1991) Detection of Epstein-Barr virus genomes in Hodgkin's disease: relation to age. J Clin Pathol 44:844–848 Jarrett RF, Armstrong AA, Alexander E (1996) Epidemiology of EBV and Hodgkin’s lymphoma. Ann Oncol 7(Suppl 4):5–10 Glaser SL, Lin RJ, Stewart SL et al (1997) Epstein- Barr virus-associated Hodgkin’s disease: epidemiologic characteristics in international data. Int J Cancer 70:375–382 Longnecker R, Kieff E, Cohen JI (2013) Epstein- Barr Virus. In: Fields BN, Knipe DM, Howley PM (eds) Fields’ virology, 2nd edn. Lippincott Williams & Wilkins, Philadelphia, PA, pp R1898–RR954 de-The G, Day NE, Geser A et al (1975) Sero- epidemiology of the Epstein-Barr virus: preliminary analysis of an international study – a review. IARC Sci Publ 11:3–16 Young LS, Yap LF, Murray PG (2016) Epstein-Barr virus: more than 50 years old and still providing surprises. Nat Rev Cancer 16:789–802 Farrell PJ (2018) Epstein-Barr virus and cancer. Annu Rev Pathol 14:29–53 Babcock GJ, Decker LL, Volk M, Thorley-Lawson DA (1998) EBV persistence in memory B cells in vivo. Immunity 9:395–404 Rickinson AB, Long HM, Palendira U, Munz C, Hislop AD (2014) Cellular immune controls over Epstein-Barr virus infection: new lessons from the clinic and the laboratory. Trends Immunol 35:159–169 Skalsky RL, Cullen BR (2015) EBV noncoding RNAs. Curr Top Microbiol Immunol 391:181–217 Pfeffer S, Zavolan M, Grasser FA et al (2004) Identification of virus-encoded microRNAs. Science 304:734–736 Cai X, Schafer A, Lu S et al (2006) Epstein-Barr virus microRNAs are evolutionarily conserved and differentially expressed. PLoS Pathog 2:e23 Edwards RH, Marquitz AR, Raab-Traub N (2008) Epstein-Barr virus BART microRNAs are produced from a large intron prior to splicing. J Virol 82:9094–9106 Zhu JY, Pfuhl T, Motsch N et al (2009) Identification of novel Epstein-Barr virus microRNA genes from nasopharyngeal carcinomas. J Virol 83:3333–3341 Cosmopoulos K, Pegtel M, Hawkins J et al (2009) Comprehensive profiling of Epstein-Barr virus microRNAs in nasopharyngeal carcinoma. J Virol 83:2357–2367 2 The Role of Viruses in the Genesis of Hodgkin Lymphoma 22. Klinke O, Feederle R, Delecluse HJ (2014) Genetics of Epstein-Barr virus microRNAs. Semin Cancer Biol 26:52–59 23. Khanna R, Burrows SR (2000) Role of cytotoxic T lymphocytes in Epstein-Barr virus-associated diseases. Annu Rev Microbiol 54:19–48 24. Hislop AD, Taylor GS, Sauce D, Rickinson AB (2007) Cellular responses to viral infection in humans: lessons from Epstein-Barr virus. Annu Rev Immunol 25:587–617 25. Pallesen G, Hamilton-Dutoit SJ, Rowe M, Young LS (1991) Expression of Epstein-Barr virus latent gene products in tumour cells of Hodgkin’s disease. Lancet 337:320–322 26. Wu TC, Mann RB, Charache P et al (1990) Detection of EBV gene expression in Reed-Sternberg cells of Hodgkin’s disease. Int J Cancer 46:801–804 27. Weiss LM, Movahed LA, Warnke RA, Sklar J (1989) Detection of Epstein-Barr viral genomes in ReedSternberg cells of Hodgkin’s disease. N Engl J Med 320:502–506 28. Weiss LM, Strickler JG, Warnke RA, Purtilo DT, Sklar J (1987) Epstein-Barr viral DNA in tissues of Hodgkin’s disease. Am J Pathol 129:86–91 29. Gledhill S, Gallagher A, Jones DB et al (1991) Viral involvement in Hodgkin’s disease: detection of clonal type a Epstein-Barr virus genomes in tumour samples. Br J Cancer 64:227–232 30. Grasser FA, Murray PG, Kremmer E et al (1994) Monoclonal antibodies directed against the Epstein- Barr virus-encoded nuclear antigen 1 (EBNA1): immunohistologic detection of EBNA1 in the malignant cells of Hodgkin’s disease. Blood 84:3792–3798 31. Deacon EM, Pallesen G, Niedobitek G et al (1993) Epstein-Barr virus and Hodgkin’s disease: transcriptional analysis of virus latency in the malignant cells. J Exp Med 177:339–349 32. Niedobitek G, Kremmer E, Herbst H et al (1997) Immunohistochemical detection of the Epstein- Barr virus-encoded latent membrane protein 2A in Hodgkin’s disease and infectious mononucleosis. Blood 90:1664–1672 33. Qiu J, Cosmopoulos K, Pegtel M et al (2011) A novel persistence associated EBV miRNA expression profile is disrupted in neoplasia. PLoS Pathog 7:e1002193 34. Kuppers R (2009) The biology of Hodgkin’s lymphoma. Nat Rev Cancer 9:15–27 35. Kuppers R (2009) Molecular biology of Hodgkin lymphoma. Hematology Am Soc Hematol Educ Program 2009:491–496 36. Kuppers R, Klein U, Schwering I et al (2003) Identification of Hodgkin and Reed-Sternberg cellspecific genes by gene expression profiling. J Clin Invest 111:529–537 37. Schwering I, Brauninger A, Klein U et al (2003) Loss of the B-lineage-specific gene expression program in Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma. Blood 101:1505–1512 39 38. Bechtel D, Kurth J, Unkel C, Kuppers R (2005) Transformation of BCR-deficient germinal-center B cells by EBV supports a major role of the virus in the pathogenesis of Hodgkin and posttransplantation lymphomas. Blood 106:4345–4350 39. Mancao C, Altmann M, Jungnickel B, Hammerschmidt W (2005) Rescue of “crippled” germinal center B cells from apoptosis by Epstein- Barr virus. Blood 106:4339–4344 40. Chaganti S, Bell AI, Pastor NB et al (2005) Epstein- Barr virus infection in vitro can rescue germinal center B cells with inactivated immunoglobulin genes. Blood 106:4249–4252 41. Mancao C, Hammerschmidt W (2007) Epstein-Barr virus latent membrane protein 2A is a B-cell receptor mimic and essential for B-cell survival. Blood 110:3715–3721 42. Caldwell RG, Brown RC, Longnecker R (2000) Epstein-Barr virus LMP2A-induced B-cell survival in two unique classes of EmuLMP2A transgenic mice. J Virol 74:1101–1113 43. Portis T, Longnecker R (2003) Epstein-Barr virus LMP2A interferes with global transcription factor regulation when expressed during B-lymphocyte development. J Virol 77:105–114 44. Anderson LJ, Longnecker R (2009) Epstein-Barr virus latent membrane protein 2A exploits Notch1 to alter B-cell identity in vivo. Blood 113:108–116 45. Portis T, Dyck P, Longnecker R (2003) EpsteinBarr Virus (EBV) LMP2A induces alterations in gene transcription similar to those observed in Reed-Sternberg cells of Hodgkin lymphoma. Blood 102:4166–4178 46. Basso K, Klein U, Niu H et al (2004) Tracking CD40 signaling during germinal center development. Blood 104:4088–4096 47. Devergne O, Cahir McFarland ED, Mosialos G, Izumi KM, Ware CF, Kieff E (1998) Role of the TRAF binding site and NF-kappaB activation in Epstein- Barr virus latent membrane protein 1-induced cell gene expression. J Virol 72:7900–7908 48. Izumi KM, Kieff ED (1997) The Epstein-Barr virus oncogene product latent membrane protein 1 engages the tumor necrosis factor receptor-associated death domain protein to mediate B lymphocyte growth transformation and activate NF-kappaB. Proc Natl Acad Sci U S A 94:12592–12597 49. Kieser A, Kilger E, Gires O, Ueffing M, Kolch W, Hammerschmidt W (1997) Epstein-Barr virus latent membrane protein-1 triggers AP-1 activity via the c-Jun N-terminal kinase cascade. EMBO J 16:6478–6485 50. Eliopoulos AG, Young LS (1998) Activation of the cJun N-terminal kinase (JNK) pathway by the Epstein-Barr virus-encoded latent membrane protein 1 (LMP1). Oncogene 16:1731–1742 51. Eliopoulos AG, Gallagher NJ, Blake SM, Dawson CW, Young LS (1999) Activation of the p38 mitogen- activated protein kinase pathway by R. F. Jarrett et al. 40 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. Epstein-Barr virus-encoded latent membrane protein 1 coregulates interleukin-6 and interleukin-8 production. J Biol Chem 274:16085–16096 Vockerodt M, Morgan SL, Kuo M et al (2008) The Epstein-Barr virus oncoprotein, latent membrane protein-1, reprograms germinal centre B cells towards a Hodgkin’s Reed-Sternberg-like phenotype. J Pathol 216:83–92 Bargou RC, Emmerich F, Krappmann D et al (1997) Constitutive nuclear factor-kappaB-RelA activation is required for proliferation and survival of Hodgkin’s disease tumor cells. J Clin Invest 100:2961–2969 Dutton A, O'Neil JD, Milner AE et al (2004) Expression of the cellular FLICE-inhibitory protein (c-FLIP) protects Hodgkin’s lymphoma cells from autonomous Fas-mediated death. Proc Natl Acad Sci U S A 101:6611–6616 Kashkar H, Haefs C, Shin H et al (2003) XIAP- mediated caspase inhibition in Hodgkin’s lymphoma-derived B cells. J Exp Med 198:341–347 Nanbo A, Sugden A, Sugden B (2007) The coupling of synthesis and partitioning of EBV’s plasmid replicon is revealed in live cells. EMBO J 26:4252–4262 Kennedy G, Komano J, Sugden B (2003) Epstein- Barr virus provides a survival factor to Burkitt’s lymphomas. Proc Natl Acad Sci U S A 100:14269–14274 Wilson JB, Bell JL, Levine AJ (1996) Expression of Epstein-Barr virus nuclear antigen-1 induces B cell neoplasia in transgenic mice. EMBO J 15:3117–3126 Kang MS, Lu H, Yasui T et al (2005) Epstein-Barr virus nuclear antigen 1 does not induce lymphoma in transgenic FVB mice. Proc Natl Acad Sci U S A 102:820–825 Kang MS, Soni V, Bronson R, Kieff E (2008) Epstein-Barr virus nuclear antigen 1 does not cause lymphoma in C57BL/6J mice. J Virol 82:4180–4183 Yajima M, Kanda T, Takada K (2005) Critical role of Epstein-Barr Virus (EBV)-encoded RNA in efficient EBV-induced B-lymphocyte growth transformation. J Virol 79:4298–4307 Skalsky RL, Corcoran DL, Gottwein E et al (2012) The viral and cellular microRNA targetome in lymphoblastoid cell lines. PLoS Pathog 8:e1002484 Hancock MH, Skalsky RL (2018) Roles of noncoding RNAs during herpesvirus infection. Curr Top Microbiol Immunol 419:243–280 Albanese M, Tagawa T, Buschle A, Hammerschmidt W (2017) MicroRNAs of Epstein-Barr virus control innate and adaptive antiviral immunity. J Virol 91:pii: e01667 Chen Y, Fachko D, Ivanov NS, Skinner CM, Skalsky RL (2019) Epstein-Barr virus microRNAs regulate B cell receptor signal transduction and lytic reactivation. PLoS Pathog 15:e1007535 Murer A, Ruhl J, Zbinden A et al (2019) MicroRNAs of Epstein-Barr virus attenuate T-cell-mediated immune control in vivo. MBio 10:e01941–e01918 Ross N, Gandhi MK, Nourse JP (2013) The Epstein- Barr virus microRNA BART11-5p targets the early 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. B-cell transcription factor EBF1. Am J Blood Res 3:210–224 Godshalk SE, Bhaduri-McIntosh S, Slack FJ (2008) Epstein-Barr virus-mediated dysregulation of human microRNA expression. Cell Cycle 7:3595–3600 van den Berg A, Kroesen BJ, Kooistra K et al (2003) High expression of B-cell receptor inducible gene BIC in all subtypes of Hodgkin lymphoma. Genes Chromosomes Cancer 37:20–28 Navarro A, Gaya A, Martinez A et al (2008) MicroRNA expression profiling in classic Hodgkin lymphoma. Blood 111:2825–2832 Vrazo AC, Chauchard M, Raab-Traub N, Longnecker R (2012) Epstein-Barr virus LMP2A reduces hyperactivation induced by LMP1 to restore normal B cell phenotype in transgenic mice. PLoS Pathog 8:e1002662 Vrzalikova K, Ibrahim M, Nagy E et al (2018) Co-expression of the Epstein-Barr Virus-encoded latent membrane proteins and the pathogenesis of classic Hodgkin lymphoma. Cancers (Basel) 10:285 Wirtz T, Weber T, Kracker S, Sommermann T, Rajewsky K, Yasuda T (2016) Mouse model for acute Epstein-Barr virus infection. Proc Natl Acad Sci U S A 113:13821–13826 Greaves P, Clear A, Owen A et al (2013) Defining characteristics of classical Hodgkin lymphoma microenvironment T-helper cells. Blood 122:2856–2863 Morales O, Mrizak D, Francois V et al (2014) Epstein-Barr virus infection induces an increase of T regulatory type 1 cells in Hodgkin lymphoma patients. Br J Haematol 166:875–890 Oudejans JJ, Jiwa NM, Kummer JA et al (1996) Analysis of major histocompatibility complex class I expression on Reed-Sternberg cells in relation to the cytotoxic T-cell response in Epstein-Barr viruspositive and -negative Hodgkin’s disease. Blood 87:3844–3851 Barros MH, Segges P, Vera-Lozada G, Hassan R, Niedobitek G (2015) Macrophage polarization reflects T cell composition of tumor microenvironment in pediatric classical Hodgkin lymphoma and has impact on survival. PLoS One 10:e0124531 Kis LL, Takahara M, Nagy N, Klein G, Klein E (2006) Cytokine mediated induction of the major Epstein-Barr virus (EBV)-encoded transforming protein, LMP-1. Immunol Lett 104:83–88 Dukers DF, Jaspars LH, Vos W et al (2000) Quantitative immunohistochemical analysis of cytokine profiles in Epstein-Barr virus-positive and -negative cases of Hodgkin’s disease. J Pathol 190:143–149 Khanna R, Burrows SR, Nicholls J, Poulsen LM (1998) Identification of cytotoxic T cell epitopes within Epstein-Barr virus (EBV) oncogene latent membrane protein 1 (LMP1): evidence for HLA A2 supertype-restricted immune recognition of EBV- infected cells by LMP1-specific cytotoxic T lymphocytes. Eur J Immunol 28:451–458 2 The Role of Viruses in the Genesis of Hodgkin Lymphoma 81. Lee SP, Thomas WA, Murray RJ et al (1993) HLA A2.1-restricted cytotoxic T cells recognizing a range of Epstein-Barr virus isolates through a defined epitope in latent membrane protein LMP2. J Virol 67:7428–7435 82. Green MR, Rodig S, Juszczynski P et al (2012) Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: implications for targeted therapy. Clin Cancer Res 18:1611–1618 83. Nakagomi H, Dolcetti R, Bejarano MT, Pisa P, Kiessling R, Masucci MG (1994) The Epstein-Barr virus latent membrane protein-1 (LMP1) induces interleukin-10 production in Burkitt lymphoma lines. Int J Cancer 57:240–244 84. Cader FZ, Vockerodt M, Bose S et al (2013) The EBV oncogene LMP1 protects lymphoma cells from cell death through the collagen-mediated activation of DDR1. Blood 122:4237–4245 85. Jarrett RF, Krajewski AS, Angus B et al (2003) The Scotland and Newcastle epidemiological study of Hodgkin’s disease: impact of histopathological review and EBV status on incidence estimates. J Clin Pathol 56:811–816 86. Lee JH, Kim Y, Choi JW, Kim YS (2014) Prevalence and prognostic significance of Epstein-Barr virus infection in classical Hodgkin’s lymphoma: a meta- analysis. Arch Med Res 45:417–431 87. Armstrong AA, Alexander FE, Paes RP et al (1993) Association of Epstein-Barr virus with pediatric Hodgkin’s disease. Am J Pathol 142:1683–1688 88. Flavell K, Constandinou C, Lowe D et al (1999) Effect of material deprivation on Epstein-Barr virus infection in Hodgkin’s disease in the west midlands. Br J Cancer 80:604–608 89. Henle G, Henle W, Clifford P et al (1969) Antibodies to Epstein-Barr virus in Burkitt’s lymphoma and control groups. J Natl Cancer Inst 43:1147–1157 90. Crawford DH, Macsween KF, Higgins CD et al (2006) A cohort study among university students: identification of risk factors for Epstein-Barr virus seroconversion and infectious mononucleosis. Clin Infect Dis 43:276–282 91. Alexander FE, Jarrett RF, Lawrence D et al (2000) Risk factors for Hodgkin’s disease by Epstein-Barr virus (EBV) status: prior infection by EBV and other agents. Br J Cancer 82:1117–1121 92. Hjalgrim H, Askling J, Rostgaard K et al (2003) Characteristics of Hodgkin’s lymphoma after infectious mononucleosis. N Engl J Med 349:1324–1332 93. Hjalgrim H, Smedby KE, Rostgaard K et al (2007) Infectious mononucleosis, childhood social environment, and risk of Hodgkin lymphoma. Cancer Res 67:2382–2388 94. Glaser SL, Clarke CA, Gulley ML et al (2003) Population-based patterns of human immunodeficiency virus-related Hodgkin lymphoma in the greater San Francisco Bay Area, 1988–1998. Cancer 98:300–309 41 95. Quinlan SC, Landgren O, Morton LM, Engels EA (2010) Hodgkin lymphoma among US solid organ transplant recipients. Transplantation 90:1011–1015 96. Jarrett RF (2002) Viruses and Hodgkin’s lymphoma. Ann Oncol 13(Suppl 1):23–29 97. Levin LI, Chang ET, Ambinder RF et al (2012) Atypical prediagnosis Epstein-Barr virus serology restricted to EBV-positive Hodgkin lymphoma. Blood 120:3750–3755 98. Chang ET, Zheng T, Lennette ET et al (2004) Heterogeneity of risk factors and antibody profiles in Epstein-Barr virus genome-positive and -negative Hodgkin lymphoma. J Infect Dis 189:2271–2281 99. Henle W, Henle G, Andersson J et al (1987) Antibody responses to Epstein-Barr virus-determined nuclear antigen (EBNA)-1 and EBNA-2 in acute and chronic Epstein-Barr virus infection. Proc Natl Acad Sci U S A 84:570–574 100. Rubicz R, Yolken R, Drigalenko E et al (2013) A genome-wide integrative genomic study localizes genetic factors influencing antibodies against Epstein-Barr virus nuclear antigen 1 (EBNA-1). PLoS Genet 9:e1003147 101. Diepstra A, Niens M, Vellenga E et al (2005) Association with HLA class I in Epstein-Barr- virus-positive and with HLA class III in Epstein- Barr- virus-negative Hodgkin’s lymphoma. Lancet 365:2216–2224 102. Niens M, Jarrett RF, Hepkema B et al (2007) HLA- A∗02 is associated with a reduced risk and HLA- A∗01 with an increased risk of developing EBV+ Hodgkin lymphoma. Blood 110:3310–3315 103. Hjalgrim H, Rostgaard K, Johnson PC et al (2010) HLA-A alleles and infectious mononucleosis suggest a critical role for cytotoxic T-cell response in EBV-related Hodgkin lymphoma. Proc Natl Acad Sci U S A 107:6400–6405 104. Urayama KY, Jarrett RF, Hjalgrim H et al (2012) Genome-wide association study of classical Hodgkin lymphoma and Epstein-Barr virus status- defined subgroups. J Natl Cancer Inst 104:240–253 105. Huang X, Kushekhar K, Nolte I et al (2012) HLA associations in classical Hodgkin lymphoma: EBV status matters. PLoS One 7:e39986 106. Huang X, Hepkema B, Nolte I et al (2012) HLA- A∗02:07 is a protective allele for EBV negative and a susceptibility allele for EBV positive classical Hodgkin lymphoma in China. PLoS One 7:e31865 107. Johnson PC, McAulay KA, Montgomery D et al (2015) Modeling HLA associations with EBV- positive and -negative Hodgkin lymphoma suggests distinct mechanisms in disease pathogenesis. Int J Cancer 137:1066–1075 108. Delahaye-Sourdeix M, Urayama KY, Gaborieau V et al (2015) A novel risk locus at 6p21.3 for Epstein- Barr virus-positive Hodgkin lymphoma. Cancer Epidemiol Biomark Prev 24:1838–1843 109. Brennan RM, Burrows SR (2008) A mechanism for the HLA-A∗01-associated risk for EBV+ Hodgkin R. F. Jarrett et al. 42 110. 111. 112. 113. 114. 115. 116. 117. 118. 119. 120. 121. 122. 123. lymphoma and infectious mononucleosis. Blood 112:2589–2590 Alexander FE, Lawrence DJ, Freeland J et al (2003) An epidemiologic study of index and family infectious mononucleosis and adult Hodgkin’s disease (HD): evidence for a specific association with EBV+ve HD in young adults. Int J Cancer 107:298–302 McAulay KA, Higgins CD, Macsween KF et al (2007) HLA class I polymorphisms are associated with development of infectious mononucleosis upon primary EBV infection. J Clin Invest 117:3042–3048 Khan G, Lake A, Shield L et al (2005) Phenotype and frequency of Epstein-Barr virus-infected cells in pretreatment blood samples from patients with Hodgkin lymphoma. Br J Haematol 129:511–519 Hochberg D, Souza T, Catalina M, Sullivan JL, Luzuriaga K, Thorley-Lawson DA (2004) Acute infection with Epstein-Barr virus targets and overwhelms the peripheral memory B-cell compartment with resting, latently infected cells. J Virol 78:5194–5204 Cohen JI, Mocarski ES, Raab-Traub N, Corey L, Nabel GJ (2013) The need and challenges for development of an Epstein-Barr virus vaccine. Vaccine 31(Suppl 2):B194–B196 Khan G, Miyashita EM, Yang B, Babcock GJ, Thorley-Lawson DA (1996) Is EBV persistence in vivo a model for B cell homeostasis? Immunity 5:173–179 Brauninger A, Schmitz R, Bechtel D, Renne C, Hansmann ML, Kuppers R (2006) Molecular biology of Hodgkin’s and Reed/Sternberg cells in Hodgkin’s lymphoma. Int J Cancer 118:1853–1861 Montgomery ND, Coward WB, Johnson S et al (2016) Karyotypic abnormalities associated with Epstein-Barr virus status in classical Hodgkin lymphoma. Cancer Genet 209:408–416 Tiacci E, Ladewig E, Schiavoni G et al (2018) Pervasive mutations of JAK-STAT pathway genes in classical Hodgkin lymphoma. Blood 131:2454–2465 Schmitz R, Hansmann ML, Bohle V et al (2009) TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin lymphoma and primary mediastinal B cell lymphoma. J Exp Med 206:981–989 Cabannes E, Khan G, Aillet F, Jarrett RF, Hay RT (1999) Mutations in the IkBa gene in Hodgkin’s disease suggest a tumour suppressor role for IkappaBalpha. Oncogene 18:3063–3070 Emmerich F, Meiser M, Hummel M et al (1999) Overexpression of I kappa B alpha without inhibition of NF-kappaB activity and mutations in the I kappa B alpha gene in Reed-Sternberg cells. Blood 94:3129–3134 Jungnickel B, Staratschek-Jox A, Brauninger A et al (2000) Clonal deleterious mutations in the IkappaBalpha gene in the malignant cells in Hodgkin’s lymphoma. J Exp Med 191:395–402 Lake A, Shield LA, Cordano P et al (2009) Mutations of NFKBIA, encoding IkappaB alpha, are a recur- 124. 125. 126. 127. 128. 129. 130. 131. 132. 133. 134. 135. 136. rent finding in classical Hodgkin lymphoma but are not a unifying feature of non-EBV-associated cases. Int J Cancer 125:1334–1342 Enciso-Mora V, Broderick P, Ma Y et al (2010) A genome-wide association study of Hodgkin’s lymphoma identifies new susceptibility loci at 2p16.1 (REL), 8q24.21 and 10p14 (GATA3). Nat Genet 42:1126–1130 Cozen W, Timofeeva MN, Li D et al (2014) A meta- analysis of Hodgkin lymphoma reveals 19p13.3 TCF3 as a novel susceptibility locus. Nat Commun 5:3856 Tiacci E, Doring C, Brune V et al (2012) Analyzing primary Hodgkin and Reed-Sternberg cells to capture the molecular and cellular pathogenesis of classical Hodgkin lymphoma. Blood 120:4609–4620 Clarke CA, Glaser SL, Dorfman RF et al (2001) Epstein-Barr virus and survival after Hodgkin disease in a population-based series of women. Cancer 91:1579–1587 Jarrett RF, Stark GL, White J et al (2005) Impact of tumor Epstein-Barr virus status on presenting features and outcome in age-defined subgroups of patients with classic Hodgkin lymphoma: a population-based study. Blood 106:2444–2451 Keegan TH, Glaser SL, Clarke CA et al (2005) Epstein-Barr virus as a marker of survival after Hodgkin’s lymphoma: a population-based study. J Clin Oncol 23:7604–7613 Diepstra A, van Imhoff GW, Schaapveld M et al (2009) Latent Epstein-Barr virus infection of tumor cells in classical Hodgkin’s lymphoma predicts adverse outcome in older adult patients. J Clin Oncol 27:3815–3821 Gallagher A, Armstrong AA, MacKenzie J et al (1999) Detection of Epstein-Barr virus (EBV) genomes in the serum of patients with EBV- associated Hodgkin’s disease. Int J Cancer 84:442–448 Kanakry J, Ambinder R (2015) The biology and clinical utility of EBV monitoring in blood. Curr Top Microbiol Immunol 391:475–499 Gutensohn N, Cole P (1977) Epidemiology of Hodgkin’s disease in the young. Int J Cancer 19:595–604 Glaser SL, Keegan TH, Clarke CA et al (2005) Exposure to childhood infections and risk of Epstein-Barr virus--defined Hodgkin’s lymphoma in women. Int J Cancer 115:599–605 Gallagher A, Perry J, Freeland J et al (2003) Hodgkin lymphoma and Epstein-Barr virus (EBV): no evidence to support hit-and-run mechanism in cases classified as non-EBV-associated. Int J Cancer 104:624–630 Staratschek-Jox A, Kotkowski S, Belge G et al (2000) Detection of Epstein-Barr virus in HodgkinReed-Sternberg cells: no evidence for the persistence of integrated viral fragments in latent membrane protein-1 (LMP-1)-negative classical Hodgkin’s disease. Am J Pathol 156:209–216 2 The Role of Viruses in the Genesis of Hodgkin Lymphoma 137. Cozen W, Yu G, Gail MH et al (2013) Fecal microbiota diversity in survivors of adolescent/young adult Hodgkin lymphoma: a study of twins. Br J Cancer 108:1163–1167 138. Armstrong AA, Shield L, Gallagher A, Jarrett RF (1998) Lack of involvement of known oncogenic DNA viruses in Epstein-Barr virus-negative Hodgkin’s disease. Br J Cancer 77:1045–1047 139. Schmidt CA, Oettle H, Peng R et al (2000) Presence of human beta- and gamma-herpes virus DNA in Hodgkin’s disease. Leuk Res 24:865–870 140. Gallagher A, Perry J, Shield L, Freeland J, MacKenzie J, Jarrett RF (2002) Viruses and Hodgkin disease: no evidence of novel herpesviruses in non-EBV-associated lesions. Int J Cancer 101:259–264 141. Benavente Y, Mbisa G, Labo N et al (2011) Antibodies against lytic and latent Kaposi’s sarcoma- associated herpes virus antigens and lymphoma in the European EpiLymph case-control study. Br J Cancer 105:1768–1771 142. Samoszuk M, Ravel J (1991) Frequent detection of Epstein-Barr viral deoxyribonucleic acid and absence of cytomegalovirus deoxyribonucleic acid in Hodgkin’s disease and acquired immunodeficiency syndrome-related Hodgkin’s disease. Lab Investig 65:631–636 143. Lin SH, Yeh HM, Tzeng CH, Chen PM (1993) Immunoglobulin and T cell receptor beta chain gene rearrangements and Epstein-Barr viral DNA in tissues of Hodgkin’s disease in Taiwan. Int J Hematol 57:251–257 144. Hernandez-Losa J, Fedele CG, Pozo F et al (2005) Lack of association of polyomavirus and herpesvirus types 6 and 7 in human lymphomas. Cancer 103:293–298 145. Secchiero P, Bonino LD, Lusso P et al (1998) Human herpesvirus type 7 in Hodgkin’s disease. Br J Haematol 101:492–499 146. Berneman ZN, Torelli G, Luppi M, Jarrett RF (1998) Absence of a directly causative role for human herpesvirus 7 in human lymphoma and a review of human herpesvirus 6 in human malignancy. Ann Hematol 77:275–278 147. Ablashi D, Agut H, Alvarez-Lafuente R et al (2014) Classification of HHV-6A and HHV-6B as distinct viruses. Arch Virol 159:863–870 148. Ablashi DV, Josephs SF, Buchbinder A et al (1988) Human B-lymphotropic virus (human herpesvirus6). J Virol Methods 21:29–48 149. Clark DA, Alexander FE, McKinney PA et al (1990) The seroepidemiology of human herpesvirus-6 (HHV-6) from a case-control study of leukaemia and lymphoma. Int J Cancer 45:829–833 150. Torelli G, Marasca R, Luppi M et al (1991) Human herpesvirus-6 in human lymphomas: identification of specific sequences in Hodgkin’s lymphomas by polymerase chain reaction. Blood 77:2251–2258 151. Di Luca D, Dolcetti R, Mirandola P et al (1994) Human herpesvirus 6: a survey of presence and 152. 153. 154. 155. 156. 157. 158. 159. 160. 161. 162. 163. 164. 165. 43 variant distribution in normal peripheral lymphocytes and lymphoproliferative disorders. J Infect Dis 170:211–215 Valente G, Secchiero P, Lusso P et al (1996) Human herpesvirus 6 and Epstein-Barr virus in Hodgkin’s disease: a controlled study by polymerase chain reaction and in situ hybridization. Am J Pathol 149:1501–1510 Kashanchi F, Araujo J, Doniger J et al (1997) Human herpesvirus 6 (HHV-6) ORF-1 transactivating gene exhibits malignant transforming activity and its protein binds to p53. Oncogene 14:359–367 Collot S, Petit B, Bordessoule D et al (2002) Real- time PCR for quantification of human herpesvirus 6 DNA from lymph nodes and saliva. J Clin Microbiol 40:2445–2451 Lacroix A, Jaccard A, Rouzioux C et al (2007) HHV-6 and EBV DNA quantitation in lymph nodes of 86 patients with Hodgkin’s lymphoma. J Med Virol 79:1349–1356 Siddon A, Lozovatsky L, Mohamed A, Hudnall SD (2012) Human herpesvirus 6 positive ReedSternberg cells in nodular sclerosis Hodgkin lymphoma. Br J Haematol 158:635–643 Daibata M, Taguchi T, Nemoto Y, Taguchi H, Miyoshi I (1999) Inheritance of chromosomally integrated human herpesvirus 6 DNA. Blood 94:1545–1549 Leong HN, Tuke PW, Tedder RS et al (2007) The prevalence of chromosomally integrated human herpesvirus 6 genomes in the blood of UK blood donors. J Med Virol 79:45–51 Kaufer BB, Flamand L (2014) Chromosomally integrated HHV-6: impact on virus, cell and organismal biology. Curr Opin Virol 9:111–118 Luppi M, Barozzi P, Marasca R, Ceccherini-Nelli L, Torelli G (1993) Characterization of human herpesvirus 6 genomes from cases of latent infection in human lymphomas and immune disorders. J Infect Dis 168:1074–1075 Maeda A, Sata T, Enzan H et al (1993) The evidence of human herpesvirus 6 infection in the lymph nodes of Hodgkin’s disease. Virchows Arch A Pathol Anat Histopathol 423:71–75 Rojo J, Ferrer Argote VE, Klueppelberg U et al (1994) Semi-quantitative in situ hybridization and immunohistology for antigen expression of human herpesvirus-6 in various lymphoproliferative diseases. In Vivo 8:517–526 Luppi M, Barozzi P, Garber R et al (1998) Expression of human herpesvirus-6 antigens in benign and malignant lymphoproliferative diseases. Am J Pathol 153:815–823 Lacroix A, Collot-Teixeira S, Mardivirin L et al (2010) Involvement of human herpesvirus-6 variant B in classic Hodgkin’s lymphoma via DR7 oncoprotein. Clin Cancer Res 16:4711–4721 Thompson J, Choudhury S, Kashanchi F et al (1994) A transforming fragment within the direct repeat region of human herpesvirus type 6 that transactivates HIV-1. Oncogene 9:1167–1175 44 166. Schleimann MH, Hoberg S, Solhoj Hansen A et al (2014) The DR6 protein from human herpesvirus6B induces p53-independent cell cycle arrest in G2/M. Virology 452-453:254–263 167. Megaw AG, Rapaport D, Avidor B, Frenkel N, Davison AJ (1998) The DNA sequence of the RK strain of human herpesvirus 7. Virology 244:119–132 168. Luppi M, Marasca R, Barozzi P et al (1993) Three cases of human herpesvirus-6 latent infection: integration of viral genome in peripheral blood mononuclear cell DNA. J Med Virol 40:44–52 169. Torelli G, Barozzi P, Marasca R et al (1995) Targeted integration of human herpesvirus 6 in the p arm of chromosome 17 of human peripheral blood mononuclear cells in vivo. J Med Virol 46:178–188 170. Bell AJ, Gallagher A, Mottram T et al (2014) Germ- line transmitted, chromosomally integrated HHV-6 and classical Hodgkin lymphoma. PLoS One 9:e112642 171. Tang H, Serada S, Kawabata A et al (2013) CD134 is a cellular receptor specific for human herpesvirus6B entry. Proc Natl Acad Sci U S A 110:9096–9099 172. Ehlers B, Borchers K, Grund C, Frolich K, Ludwig H, Buhk HJ (1999) Detection of new DNA polymerase genes of known and potentially novel herpesviruses by PCR with degenerate and deoxyinosine- substituted primers. Virus Genes 18:211–220 173. Jarrett RF, Johnson D, Wilson KS, Gallagher A (2006) Molecular methods for virus discovery. Dev Biol (Basel) 123:77–88. discussion 119–132 174. Allander T, Andreasson K, Gupta S et al (2007) Identification of a third human polyomavirus. J Virol 81:4130–4136 175. Feng H, Shuda M, Chang Y, Moore PS (2008) Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 319:1096–1100 176. Ehlers B, Wieland U (2013) The novel human polyomaviruses HPyV6, 7, 9 and beyond. APMIS 121:783–795 177. Gaynor AM, Nissen MD, Whiley DM et al (2007) Identification of a novel polyomavirus from patients with acute respiratory tract infections. PLoS Pathog 3:e64 178. Prado JCM, Monezi TA, Amorim AT, Lino V, Paladino A, Boccardo E (2018) Human polyomaviruses and cancer: an overview. Clinics (Sao Paulo) 73:e558s 179. Knowles WA, Pipkin P, Andrews N et al (2003) Population-based study of antibody to the human polyomaviruses BKV and JCV and the simian polyomavirus SV40. J Med Virol 71:115–123 180. Kean JM, Rao S, Wang M, Garcea RL (2009) Seroepidemiology of human polyomaviruses. PLoS Pathog 5:e1000363 181. Tolstov YL, Pastrana DV, Feng H et al (2009) Human Merkel cell polyomavirus infection II. MCV is a common human infection that can be detected by conformational capsid epitope immunoassays. Int J Cancer 125:1250–1256 R. F. Jarrett et al. 182. Kassem A, Schopflin A, Diaz C et al (2008) Frequent detection of Merkel cell polyomavirus in human Merkel cell carcinomas and identification of a unique deletion in the VP1 gene. Cancer Res 68:5009–5013 183. IARC (2014) Malaria and some polyomaviruses (SV40, BK, JC, and Merkel cell viruses). IARC Monogr Eval Carcinog Risks Hum 104:9–350 184. Wilson KS, Gallagher A, Freeland JM, Shield LA, Jarrett RF (2006) Viruses and Hodgkin lymphoma: no evidence of polyomavirus genomes in tumor biopsies. Leuk Lymphoma 47:1315–1321 185. Robles C, Poloczek A, Casabonne D et al (2012) Antibody response to Merkel cell polyomavirus associated with incident lymphoma in the Epilymph case-control study in Spain. Cancer Epidemiol Biomark Prev 21:1592–1598 186. Shuda M, Arora R, Kwun HJ et al (2009) Human Merkel cell polyomavirus infection I. MCV T antigen expression in Merkel cell carcinoma, lymphoid tissues and lymphoid tumors. Int J Cancer 125:1243–1249 187. Volter C, Hausen H, Alber D, de Villiers EM (1997) Screening human tumor samples with a broad- spectrum polymerase chain reaction method for the detection of polyomaviruses. Virology 237:389–396 188. Benharroch D, Shemer-Avni Y, Levy A et al (2003) New candidate virus in association with Hodgkin’s disease. Leuk Lymphoma 44:605–610 189. Benharroch D, Shemer-Avni Y, Myint YY et al (2004) Measles virus: evidence of an association with Hodgkin’s disease. Br J Cancer 91:572–579 190. Maggio E, Benharroch D, Gopas J, Dittmer U, Hansmann ML, Kuppers R (2007) Absence of measles virus genome and transcripts in Hodgkin-Reed/ Sternberg cells of a cohort of Hodgkin lymphoma patients. Int J Cancer 121:448–453 191. Wilson KS, Freeland JM, Gallagher A et al (2007) Measles virus and classical Hodgkin lymphoma: no evidence for a direct association. Int J Cancer 121:442–447 192. Karunanayake CP, Singh GV, Spinelli JJ et al (2009) Occupational exposures and Hodgkin lymphoma: Canadian case-control study. J Occup Environ Med 51:1447–1454 193. De Vlaminck I, Khush KK, Strehl C et al (2013) Temporal response of the human virome to immunosuppression and antiviral therapy. Cell 155:1178–1187 194. Freer G, Maggi F, Pifferi M, Di Cicco ME, Peroni DG, Pistello M (2018) The virome and its major component, Anellovirus, a convoluted system molding human immune defenses and possibly affecting the development of asthma and respiratory diseases in childhood. Front Microbiol 9:686 195. Jelcic I, Hotz-Wagenblatt A, Hunziker A, Zur Hausen H, de Villiers EM (2004) Isolation of multiple TT virus genotypes from spleen biopsy tissue from a Hodgkin’s disease patient: genome reorganization and diversity in the hypervariable region. J Virol 78:7498–7507 2 The Role of Viruses in the Genesis of Hodgkin Lymphoma 196. zur Hausen H, de Villiers EM (2005) Virus target cell conditioning model to explain some epidemiologic characteristics of childhood leukemias and lymphomas. Int J Cancer 115:1–5 197. Garbuglia AR, Iezzi T, Capobianchi MR et al (2003) Detection of TT virus in lymph node biopsies of B-cell lymphoma and Hodgkin’s disease, and its association with EBV infection. Int J Immunopathol Pharmacol 16:109–118 45 198. Figueiredo CP, Franz-Vasconcelos HC, Giunta G et al (2007) Detection of Torque Teno virus in EpsteinBarr virus positive and negative lymph nodes of patients with Hodgkin lymphoma. Leuk Lymphoma 48:731–735 199. Pan S, Yu T, Wang Y et al (2018) Identification of a Torque Teno Mini Virus (TTMV) in Hodgkin’s lymphoma patients. Front Microbiol 9:1680 3 Pathology and Molecular Pathology of Hodgkin Lymphoma Andreas Rosenwald and Ralf Küppers Contents 3.1 Subclassification and Pathology 3.1.1 Nodular Lymphocyte-Predominant Hodgkin Lymphoma 3.1.2 Classical Hodgkin Lymphoma: The HRS Cells 3.1.2.1 Nodular Sclerosis Classical Hodgkin Lymphoma 3.1.2.2 Mixed Cellularity Classical Hodgkin Lymphoma 3.1.2.3 Lymphocyte-Depleted Classical Hodgkin Lymphoma 3.1.2.4 Lymphocyte-Rich Classical Hodgkin Lymphoma 47 48 50 51 51 51 51 3.2 Differential Diagnosis 52 3.3 Histogenesis of HRS and LP Cells 3.3.1 Cellular Origin of HRS and LP Cells 3.3.2 Relationship of Hodgkin Cells and Reed-Sternberg Cells and Putative HRS Cell Precursors 52 52 3.4 Genetic Lesions 54 3.5 Deregulated Transcription Factor Networks and Signaling Pathways 3.5.1 The Lost B Cell Phenotype 3.5.2 Constitutive Activation of Multiple Signaling Pathways 57 57 59 3.6 Anti-apoptotic Mechanisms 60 References 61 3.1 A. Rosenwald Institute of Pathology, University of Würzburg, Würzburg, Germany e-mail: rosenwald@mail.uni-wuerzburg.de R. Küppers (*) Institute of Cell Biology (Cancer Research), Medical School, University of Duisburg-Essen, Essen, Germany e-mail: ralf.kueppers@uk-essen.de 54 Subclassification and Pathology The history of Hodgkin lymphoma (HL) dates back to the first half of the nineteenth century (see Chap. 1), and it has also been an established view for quite some time that HL comprises two different disease entities, namely, classical Hodgkin lymphoma (cHL) and nodular lymphocyte- predominant Hodgkin lymphoma (LPHL) [1]. Both entities have in common that the neoplastic © Springer Nature Switzerland AG 2020 A. Engert, A. Younes (eds.), Hodgkin Lymphoma, Hematologic Malignancies, https://doi.org/10.1007/978-3-030-32482-7_3 47 A. Rosenwald and R. Küppers 48 cell population, which can be mononucleated or multinucleated, makes up only a small percentage of all cells present in an affected lymph node. However, morphological, clinical, epidemiologic, and molecular evidence strongly support the belief that the pathogenesis of these lymphomas is distinct enough to be considered separate entities. From a diagnostic point of view, morphological details and immunohistochemistry for a selected set of markers almost always allow for a proper classification of a given lymphoma into the group of LPHL or cHL, the latter of which can be further subdivided into nodular sclerosis cHL (NSCHL), mixed cellularity cHL (MCCHL), lymphocyte-depleted cHL (LDCHL), and lymphocyte-rich cHL (LRCHL) [1]. The following sections summarize the key morphological aspects and important immunohistochemical features of HL, as well as key biological and genetic features of the HL tumor cells. For microenvironmental, clinical, and epidemiologic parameters, please refer to the respective other chapters of this book. Although the morphology of the tumor cell population of LPHL can occasionally mimic Hodgkin and Reed-Sternberg (HRS) cells of cHL, in most instances the tumor cells in LPHL, which are termed lymphocyte-predominant (LP) cells according to the current WHO classification (previously called L&H cells, for lymphocytic and/or histiocytic Reed-Sternberg (RS) cell variants), carry one large nucleus that is often multilobated (“popcorn cell”) (Fig. 3.1a). In contrast to classic HRS cells, the number of nucleoli is increased, but they are usually less prominent and less eosinophilic. LP cells are found in a nodular or follicular background that is dominated by small B lymphocytes that usually express IgD, but a more diffuse growth pattern can also be encountered, especially during progression. The follicular infiltration pattern is highlighted by the presence of CD21-positive follicular dendritic cells that tend to form a welldeveloped meshwork in the nodules. Immunohistochemically, LP cells demonstrate a complete B cell phenotype with expression of CD20, CD75, and, frequently, CD79a (Fig. 3.1b; Table 3.1). Moreover, the essential B cell transcription factors BOB.1 and OCT-2 are usually positive, and the expression of BCL6 and activation-induced cytidine deaminase (AID) is well in line with a germinal center (GC) derivation of the tumor cells, although CD10 is generally negative [1–3]. The negativity of the tumor cells for CD30, CD15, and Epstein-Barr virus (EBV) helps to distinguish LP cells from HRS cells in Fig. 3.1 Nodular lymphocyte-predominant Hodgkin lymphoma (LPHL). (a) HE-stained lymph node infiltrate showing multiple characteristic, multilobated tumor cells—termed lymphocyte-predominant (LP) cells—in a background of small lymphocytes and histiocytes (×400). (b) Strong CD20 expression in LP cells, but also in reactive, small B cells in the background (×400). Note that some of the tumor cells show rosetting by a CD20- negative lymphocyte population. These cells are T cells that often express the follicular T helper cell marker PD-1 3.1.1 Nodular Lymphocyte- Predominant Hodgkin Lymphoma 3 Pathology and Molecular Pathology of Hodgkin Lymphoma 49 Table 3.1 Genetic and phenotypic features of HRS and LP cells Feature Phenotype CD30 expression CD15 expression B cell receptor expression Loss of most B cell markers Expression of germinal center (GC) B cell markers (e.g., BCL6, activation-induced cytidine deaminase (AID)) Expression of markers for non-B cells (e.g., CD3, granzyme B, CCL17) Putative cell of origin EBV positivity Signaling pathways NF-κB activation JAK/STAT activation Aberrant expression of multiple RTKs PI3K/AKT activation AP-1 activation Genetic lesions NFKBIA mutations NFKBIE mutations TNFAIP3 mutations REL gains/amplifications MAP3K14 (NIK) gains/amplifications BCL6 translocations JAK2, PD-L1, PD-L2, JMJD2C gains/amplification STAT6 mutations, gains SOCS1 mutations PTPN1 mutations GNA13 mutations ITPKB mutations XPO1 mutations B2M mutations MHC2TA translocations SGK1 DUSP2 JUNB HRS cells LP cells Yes Yes (~70%)a No Yes Rarely Rare No Yes Modest Yes Frequently No Defective, pre-apoptotic germinal center B cell Yes (~40%) Germinal center B cell No Yes Yes Yes (~60–100%) Yes Yes Yes Yes Yes (~40%) n.a. Partly Yes (~10–20%) Yes (~10%) Yes (~40%) Yes (~50%) Yes (~25%) Rare Yes (~30%) Yes (~30%) Yes (~40%) Yes (~20%) Yes (~20%) Yes (~15%) Yes (~20%) Yes (~30%) Yes (~15%) n.a.b n.a.b n.a.b No n.a. No No n.a. Yes (~50%) No n.a. Yes (~50%) n.a. n.a. n.a. n.a. n.a. n.a. Yes (~50%) Yes (~50%) Yes (~50%) n.a. not analyzed, RTK receptor tyrosine kinase Numbers in brackets refer to the percentage of positive cases b No mutations reported in 2 whole exome sequencing studies of together 44 cases of cHL and an exome sequencing analysis of 6 cHL cell lines [8–10] a cHL, although occasionally a weak positivity for CD30 can be present in LP cells (Table 3.1). Whereas in initial lesions small B cells dominate the background, histiocytes and T cells may become more prominent during the evolution of LPHL, to an extent that LPHL may be hardly distinguishable from T cell/histiocyte-rich large B cell lymphoma (THRLBCL). “Variant histology” (e.g., depletion of small B cells in the background or unusual localization of the LP cells) appears to be associated with an inferior prognosis [4]. A prominent feature of LPHL is the often impressive rosetting of LP cells by T cells that belong to the subset of follicular T helper cells and therefore express CD57 and PD-1 [5–7]. A. Rosenwald and R. Küppers 50 3.1.2 lassical Hodgkin Lymphoma: C The HRS Cells occasionally with prominent staining of the Golgi area of the tumor cell. However, CD15 is negative in a significant proportion of cHL (20–25%) The characteristic tumor cell of cHL, the RS cell, and therefore not required to establish the diagis large and contains at least two nuclear lobes or nosis of cHL [1]. CD45 is usually negative, as are nuclei, usually with a prominent nuclear mem- the B cell transcription factors BOB.1 and OCT- brane (Fig. 3.2a). In contrast to LP cells in LPHL, 2. In the vast majority of cases, the derivation of the nucleoli of RS cells are often eosinophilic. the tumor cells from the B cell lineage is indiThe mononuclear variant of RS cells is termed cated by a nuclear positivity for the B cell-specific the Hodgkin cell. However, the morphological activator protein PAX5/BSAP, but the staining is spectrum of the tumor cell population in cHL can usually weaker compared to the staining intensity be broad and includes variants such as lacunar in the small reactive B cell population in the cells and mummified cells. In general, the tumor background of the infiltrate [11]. CD20 exprescells in cHL are called Hodgkin and Reed- sion can be observed in HRS cells in 30–40% of Sternberg cells. Immunohistochemically, the cases, but the expression is frequently restricted HRS cells stain positive for CD30 (Fig. 3.2c), to a subset of the tumor cell population, and even and CD15 is coexpressed in the majority of cases, within one HRS cell, it is of varying intensity in Fig. 3.2 Classical Hodgkin lymphoma (cHL). (a) Characteristic Hodgkin and Reed-Sternberg (HRS) cells in a mixed background of small lymphocytes, histiocytes, and eosinophils in a mixed cellularity cHL (MCCHL) (HE, ×400). (b) Nodular sclerosis subtype of cHL that demonstrates thick collagen bands surrounding the nodular infiltrates (PAS, ×20). (c) CD30 expression in HRS cells (×400). (d) Immunohistochemical staining for latent membrane protein 1 (LMP1) shows Epstein-Barr virus (EBV) association of HRS cells (×400) 3 Pathology and Molecular Pathology of Hodgkin Lymphoma different parts of the cell membrane. In comparison to CD20 expression, CD79a expression is observed less frequently [12, 13]. An EBV association, either demonstrated by immunohistochemical staining for LMP1 (latent membrane protein 1; Fig. 3.2d) or by EBER in situ hybridization, is found in a significant proportion of cHL, but the frequency varies considerably between different histological subtypes and across geographical areas [1]. Whether cHL cases exist with a bona fide derivation from the T cell lineage is currently a matter of debate. Single cases have been reported, in which a T cell receptor rearrangement could be proven in the HRS cells [14, 15], but others argue that such cases might represent only mimics of cHL which are not to be included in a disease entity that—based on fundamental principles of current lymphoma classification schemes—is of B cell derivation [16]. HRS cells reside in a cellular background that varies among the different histological subtypes of cHL which will be discussed in the following sections. 3.1.2.1 N odular Sclerosis Classical Hodgkin Lymphoma In NSCHL, affected lymph nodes frequently show a markedly thickened capsule and a nodular infiltrate whereby individual nodules are surrounded by broad collagen bands (Fig. 3.2b). HRS cells are present in a background of small lymphocytes and other nonneoplastic cells such as histiocytes and eosinophils. The number of HRS cells can vary significantly between NSCHL cases and also within a single infiltrated lymph node. Occasionally, HRS cells can form sheets that can be associated with necrosis and an intense fibrohistiocytic reaction. Morphologically, HRS cells in NSCHL often show a retraction artifact of the cytoplasmic membrane that appears to be a consequence of formalin fixation, which has led to the term “lacunar cell variant” of HRS cells. The immunohistochemical phenotype of HRS cells in NSCHL as described above is the classic phenotype; however, association with EBV is less common as compared to other cHL subtypes, especially MCCHL. 51 3.1.2.2 M ixed Cellularity Classical Hodgkin Lymphoma HRS cells in MCCHL usually have a classic morphological appearance and are scattered in a background that can contain small lymphocytes, eosinophils, neutrophils, plasma cells, and histiocytes. The infiltration pattern can be diffuse or vaguely nodular; sometimes, the lymph node architecture and especially some B cell areas are partially preserved leading to an interfollicular infiltration pattern. The characteristic features of other histologic cHL subtypes (e.g., the formation of nodular collagen bands) are absent, and, thus, MCCHL is sometimes considered as the “wastebasket” of cHL. The EBV association of HRS cells is the highest among all cHL subtypes and can reach 75% [1]. 3.1.2.3 Lymphocyte-Depleted Classical Hodgkin Lymphoma LDCHL is the rarest histological subtype of cHL (<1% of cases) and probably the most problematic one to define. It is characterized by an increased number of HRS cells present in the infiltrate and/or depletion of small lymphocytes in the nonneoplastic background population. In some cases, HRS cells are of anaplastic appearance, and in other cases, the background is composed of extensive diffuse fibrosis. However, if the pattern of fibrosis is nodular and therefore characteristic of NSCHL, a given case should be classified as NSCHL, regardless of whether there is a high number of HRS cells. Since the definition of LDCHL has changed over the past decades, some of the established clinical and biological features appear outdated in the context of the current definition. Moreover, with the increase in knowledge and the development of additional immunohistochemical markers, some of the cHL cases that were previously assigned to the LDCHL category would nowadays be included into borderline categories or even different entities [1]. 3.1.2.4 Lymphocyte-Rich Classical Hodgkin Lymphoma In LRCHL, the HRS cells are present in a lymphocyte-rich background that can be nodular or, rarely, diffuse. Often, B cell follicles are A. Rosenwald and R. Küppers 52 partially preserved with recognizable GC, and HRS cells can be found in expanded mantle and marginal zones, thus providing a B cell-rich background. HRS cells in LRCHL may resemble LP cells in LPHL morphologically to such an extent that they are indistinguishable from each other without additional immunohistochemical characterization. It is of significance that eosinophils and neutrophils should be absent from the nodular infiltrates and may only be found in low numbers in interfollicular zones and close to vascular structures. The immunophenotype of the HRS cells is classic, and an EBV association is occasionally observed, though at a lower fre quency compared to MCCHL [1]. 3.2 Differential Diagnosis In most instances, the diagnosis of LPHL and cHL is unambiguous on the basis of morphological, clinical, and, especially, immunohistochemical features (Table 3.1). However, a gray area between cHL and diffuse large B cell lymphoma (DLBCL), specifically with primary mediastinal large B cell lymphoma (PMBL), has long been known, and the most recent WHO classification introduced the category of “B cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma” [1]. It is important to note that lymphomas falling into this category are not considered a separate disease entity; rather, it was felt that lymphomas in which there is a discordance between morphological aspects of the infiltrate and the expected immunophenotype should be labeled as “intermediate” to allow a more precise definition of biological and clinical features of these lymphomas in the future. Frequently, these borderline lymphomas present with large mediastinal masses. Morphologically, they consist of large, pleomorphic B cells that grow in a sheetlike pattern in a background of a fibrotic stroma. A subset of the tumor cells may resemble HRS cells, specifically the lacunar variant, and parts of the infiltrate may correspond to the growth pattern of cHL, particularly the nodular sclerosis subtype. Immunophenotypically, there is often a preserved expression program of cHL including expression of CD30 and CD15, while markers of the B cell lineage that are often downregulated in cHL, such as CD20 and CD79a, are equally expressed in the tumor cells [1]. It is important to note that these gray zone lymphomas appear to be more common in male patients, in contrast to NSCHL and PMBL that are more frequent in females [17]. Clinically, these tumors may behave more aggressively than NSCHL and PMBL; it has to be determined in the future whether treatment regimens for aggressive B cell lymphomas or for cHL are more beneficial. The differential diagnosis between cHL and ALK-negative anaplastic large cell lymphoma (ALCL) of T cell lineage can usually be resolved using an appropriate panel of immunohistochemical markers including T cell, cytotoxic, and other markers. Problems arise when morphological features favor cHL, but tumor cells lack PAX5/ BSAP expression while cytotoxic markers are expressed. As discussed above, it is a matter of current debate whether such cases should be grouped into the cHL category or diagnosed as ALCL. Remarkably, a global gene expression study revealed surprisingly few consistent differences in the gene expression of HRS cells and ALK-negative ALCL cells [18]. Finally, EBV-associated lymphoproliferations, e.g., in the context of a coexisting T cell non-HL as well as EBV-associated DLBCL of the elderly, a subgroup of DLBCL introduced in the new WHO classification [1], can harbor HRS or HRS-like cells and therefore mimic cHL [19]. Besides other morphological and immunohistochemical features and information on the clinical setting, the pattern of EBV infection, determined by LMP1 staining or EBER in situ hybridization, might help to distinguish between these tumors. 3.3 istogenesis of HRS and LP H Cells 3.3.1 ellular Origin of HRS and LP C Cells The unusual immunophenotype of HRS cells, which does not resemble any normal hematopoietic cell, has hampered the identification of the 3 Pathology and Molecular Pathology of Hodgkin Lymphoma cellular origin of these cells considerably. Moreover, only few cell lines were available for detailed genetic studies, and the rarity of the HRS cells in the tissue posed a problem for their molecular analysis. Finally, by microdissection of HRS cells from tissue sections and single-cell polymerase chain reaction analysis of these cells, it was clarified that HRS cells derive from B cells in nearly all cases [20, 21]. This is because rearranged immunoglobulin (Ig) heavy (IgH) and light (IgL) chain gene rearrangements were detected in these cells. The detection of identical IgV gene rearrangements in the HRS cells of a given HL case also established the monoclonal nature of these cells, a hallmark of malignant cancer cells. With a few exceptions, somatic mutations were detected in the rearranged V genes of HRS cells [20–23]. As the process of somatic hypermutation, which generates such mutations, is specifically active in antigen- activated mature B cells proliferating in the GC microenvironment in the course of T-dependent immune responses [24], the presence of mutated IgV genes in the HRS cells established their derivation from GC-experienced B cells. A surprising finding was that about 25% of cases of cHL showed destructive IgV gene mutations, such as nonsense mutations or deletions causing frameshifts that rendered originally functional V region genes nonfunctional [20]. When such mutations happen in normal GC B cells, these cells quickly undergo apoptosis. On this basis, it was proposed that HRS cells in these cases derive from pre- apoptotic GC B cells that were rescued from apoptosis because they harbored or acquired some transforming events [20, 25]. It is important to note that crippling mutations, such as those generating premature stop codons, represent only a small fraction of disadvantageous IgV gene mutations that cause apoptotic death of GC B cells, and it is therefore likely that also most or even all other cases of cHL are derived from pre- apoptotic GC B cells. Even a few HL with unmutated IgV genes may derive from these precursors, because GC founder cells proliferating in GC become prone to apoptosis before the onset of somatic hypermutation activity [26]. The GC B cell origin of HRS cells was further supported by the molecular analysis of composite lymphomas, 53 composed of a cHL and a B cell non-HL. Such cases are often clonally related and show an intriguing pattern of shared as well as distinct somatic V gene mutations [27–30]. This pattern supports the assumption that both lymphomas were derived from distinct members of a proliferating GC B cell clone. A comparison of the transcriptomes of HRS cells and normal GC and extrafollicular CD30+ B cells revealed that HRS cells are in their global gene expression pattern more similar to the normal CD30+ B cells than to bulk GC B cells [31]. However, a direct derivation of HRS cells from CD30+ GC B cells seems unlikely, as CD30+ GC B cells are positively selected GC B cells with functional BCR that are preparing to return to the dark zone of the GC for a further round of proliferation and IgV gene mutation. Perhaps, in the course of their malignant transformation, the HRS cell precursors that managed to escape from apoptosis acquired the gene expression program of the positively selected and proliferation prepared CD30+ GC B cells. A few cases of cHL appear to originate from T cells, because T cell receptor gene rearrangements were detected in some cases diagnosed as HL and expressing some typical T cell molecules [14, 15]. However, it is debated whether these are true HL (see above). Remarkably, among HL cases with expression of one or more T cell markers, the majority nevertheless derives from B cells [14, 15]. The expression of multiple B cell markers by LP cells of LPHL already indicated a B cell derivation of these cells. Moreover, LP cells express several markers typically expressed by GC B cells, such as BCL6, AID, centerin, and hGAL, and the cells grow in a follicular pattern in close association with typical constituents of normal GC, i.e., follicular dendritic cells and GC-type T helper cells [2, 3, 5, 6, 32, 33]. This pointed to a close relationship between LP cells and GC B cells. This is indeed supported by the detection of clonally related and somatically mutated IgV genes in these cells [21, 34–36]. As opposed to cHL, the V genes are selected for functionality, and a fraction of cases shows ongoing somatic hypermutation during clonal expansion, a hallmark of GC B cells [21, 34, 35]. Thus, these A. Rosenwald and R. Küppers 54 findings altogether indicate a GC B cell origin of LP cells. A large-scale gene expression profiling of isolated LP cells in comparison to the main subsets of mature B cells has led to a further specification of the derivation of LP cells by showing that the gene expression pattern of LP cells resembles that of GC B cells that have already acquired some features of post-GC memory B cells [37]. 3.3.2 elationship of Hodgkin Cells R and Reed-Sternberg Cells and Putative HRS Cell Precursors The relationship of the mononucleated Hodgkin cells to the multinuclear RS cells and the potential existence of HRS precursor cells has been a matter of debate. Based on the “mixed” phenotype of HRS cells and many numerical chromosomal aberrations in these cells, it has been speculated that HRS cells as such or, specifically, the RS cells may derive from cell fusions of different cells (e.g., a B cell and a non-B cell). However, a detailed study of antigen receptor loci revealed that HRS cells do not carry more than two different alleles of these loci, which strongly supports the assumption that these cells do not derive from cell fusions [38]. Several studies of HL cell lines showed that the mononuclear Hodgkin cells give rise to the RS cells and that the latter have little proliferative activity [39–41]. Long-term time lapse-microscopy analyses revealed that mononucleated Hodgkin cells undergo incomplete cytokinesis and refusion to give rise to the multinucleated RS cells [42, 43]. Two studies reported the existence of a small subpopulation of side population cells among the mononuclear Hodgkin cells. Side population cells extrude the Hoechst dye, because they express multidrug transporters, such as MDR1 and/or ABCG2. In several types of cancers, there is an overlap between side population cells and cancer stem cells. Side population cells of cHL cell lines were CD30+CD20- and showed increased resistance against chemotherapeutic drugs [44, 45]. However, it has not yet been determined whether they have a higher capacity to sustain the HRS cell clone in long term than other mononuclear Hodgkin cells, and the fact that side population cells were not identified in all cHL cell lines analyzed argues against an essential role of these cells for the survival of the HRS cell clone. Another debated issue relates to the question whether the CD30+ typical HRS cells represent the entire tumor clone in HL or whether members of the HRS cell clones exist among small CD30– cells. An initial study for numerical chromosomal abnormalities indeed suggested that such CD30– clone members might exist [46]. However, trisomies of chromosomes as studied in that work are not a stringent clonal marker. Moreover, a molecular analysis of EBV-positive HL cases for members of the malignant clones among small, CD30– EBV+ B cells in the HL lymph nodes suggested that the small EBV+ B cells rarely, if at all, belong to the HRS cell clones [47]. Two HL cell lines were reported to contain small subpopulations of CD20+CD30–Ig+ B cells coexpressing the stem cell marker aldehyde dehydrogenase (ALDH) [48]. These cells had clonogenic potential and gave rise to the typical HRS cells of these lines. It is important to note that ALDHhigh cells were also detectable in the peripheral blood of most HL patients, and it was reported that these cells were often clonally related to the HRS cells [48]. However, the clonal relationship between the HRS cells and ALDHhigh peripheral blood B cells was not clearly shown [49], so it remains to be clarified whether ALDHhigh B cells indeed represent precursors of the HRS cell clones. A previous study using a highly sensitive PCR for HRS cell-specific Ig gene rearrangements failed to detect members of the HRS cell clone in the peripheral blood or bone marrow of two HL patients [50]. 3.4 Genetic Lesions HRS cells have a much higher number of chromosomal aberrations, including multiple numerical as well as structural abnormalities, than most other lymphomas [51]. However, it is still unclear 3 Pathology and Molecular Pathology of Hodgkin Lymphoma whether this is mostly a side effect of some type of genetic instability and whether the expression of specific oncogenes or tumor suppressor genes is recurrently affected by these lesions. When the B cell origin of HRS cells became clear, HRS cells were studied for the presence of chromosomal translocations involving the Ig loci, as such translocations are a hallmark of many B cell lymphomas. Fluorescence in situ hybridization (FISH) studies indeed provided evidence for such translocations in about 20% of cases, but most of the translocation partners involved remain to be identified [52, 53]. In a few cases, the translocation partners were BCL2, BCL3, REL, BCL6, or MYC [52–55]. Recurrent translocations affecting the major histocompatibility complex (MHC) class II transactivator (MHC2TA) were detected in about 15% of cHL cases [56]. These translocations appear to cause downregulation of MHC class II expression by HRS cells. In LPHL, translocations of the BCL6 gene have been found in about 30% of cases [57, 58]. These translocations can involve the Ig loci, but also multiple other partners [59]. Due to the difficulty to analyze the few HRS and LP cells for mutations in oncogenes and tumor suppressor genes, only relatively few of such genes have been analyzed so far in these cells. There was a major interest to understand the apoptosis resistance of HRS cells, but it turned out that mutations in the CD95 gene, an important death receptor, as well as in members of the CD95 signaling pathway (FADD, caspase 8, caspase 10) were rare or not found at all [60– 62]. Likewise, no mutations were found in the BCL2 family member BAD, and also ATM lesions are very rare [63–65]. The TP53 tumor suppressor gene was mutated in less than 10% of cases where the exons of TP53 usually carrying mutations were studied in isolated HRS cells [66, 67]. However, studies of HL cell lines indicate that HRS cells may additionally carry untypical TP53 mutations and that the frequency of TP53 mutations may therefore be higher than previously thought [68]. MDM2, a negative regulator of TP53, frequently shows gains in HRS cells, which might contribute to impaired functions of TP53 in these cells [69]. 55 Further candidate gene mutation studies revealed frequent mutations in the exportin 1 gene (XPO1) [70], which encodes a nuclear expert receptor for numerous RNAs and proteins, and inactivating mutations in and deletions of CD58 [71, 72]. CD58 is important for targeting of cells by cytotoxic T cells and NK cells, so that CD58 inactivation may contribute to immune escape of HRS cells from an attack by these cells. HRS cells show constitutive activity of the NF-κB transcription factor (see below), which is essential for the survival of these cells. The mechanisms of this activation were originally not understood. Consequently, members and regulators of this signaling pathway were studied for genetic lesions (Table 3.1). Inactivating mutations in the main NF-κB inhibitor NFKBIA (IκBα) were found in about 10–20% of HL cases and also in several HL cell lines (Fig. 3.3) [73– 76]. Recurrent mutations were also detected in another NF-κB inhibitor, NFKBIE (IκBε) [77, 78]. Inactivating mutations or deletions in two further negative regulators of NF-κB signaling, CYLD and TRAF3, have also been detected in HL cell lines and a few primary cases, but overall these events are rare [79, 80]. Moreover, HRS cells frequently harbor genomic gains or amplifications of the REL gene [81–83], encoding an NF-κB family member, and a correlation between such gains and strong REL protein expression was found [84]. The MAP3K14 gene, which encodes the NIK kinase, a major activating component of the alternative NF-κB pathway, shows gains or amplifications in about 15% of cHL [79, 85]. Also the IκB family member BCL3, which acts as a positive regulator of NF-κB activity, is affected by chromosomal gains or translocations in a small fraction of cHL [86, 87]. Somatic and clonal inactivating mutations were found in the TNFAIP3 gene in about 40% of cHL [88, 89]. TNFAIP3 encodes for the A20 protein, which is a dual ubiquitinase and deubiquitinase that functions as a negative regulator of NF-κB. It inhibits signaling from the receptor-interacting protein (RIP) and TNF receptor-associated factors (TRAFs) to the IKK kinases, which are essential mediators of NF-κB signaling. TNFAIP3 mutations were mainly found in EBV-negative cases. A. Rosenwald and R. Küppers 56 CD40 EBV infection (40%) LMP1 RANK BCMA CD40 TACI cytokine receptor CD30 RIP TRAF TNFAIP3 mutations (40%) TNFAIP3 NEMO Classical NF-κB pathway IKKα NFKBIA and NFKBIE mutations (10-20%) Alternative NF-κB pathway JAK2 gains (30%) PTPN1 IKKα IKKβ JAK IKKα SOCS1 PTPN1 mutations (20%) STAT STAT IκBα/ IκBε p50 REL amplification (40%) p50 NIK NIK gains (25%) p65 p100 RELB Proteasomal degradation BCL3 gains or translocations (rare) p65 JAK/STAT pathway SOCS1 mutations (40%) STAT6 mutations & gains (30%) cytoplasm p52 RELB nucleus BCL3 p50 p50 Fig. 3.3 NF-κB and JAK/STAT activity in HRS cells. In the classical NF-κB signaling pathway, stimulation of numerous receptors leads via TNF receptor-associated factors (TRAFs), which are often associated with the receptor-interacting protein (RIP), to activation of the IKK complex, which is composed of IKKα, IKKβ, and NEMO. The IKK complex subsequently phosphorylates the NF-κB inhibitors IκBα and IκBε. This marks them for ubiquitination and subsequent proteasomal degradation. Thereby the NF-κB transcription factors (p50/p65 or p50/ REL heterodimers) are no longer retained in the cytoplasm and translocate into the nucleus, where they activate multiple genes. The signal transduction from TRAFs/ RIP to the IKK complex can be inhibited by TNFAIP3, which removes activating ubiquitins from RIP and TRAFs and additionally links ubiquitins to these molecules to mark them for proteasomal degradation. In the alternative NF-κB pathway, activation of receptors such as CD40, BCMA, and TACI causes stimulation of the kinase NIK, which then activates an IKKα complex. Activated IKKα processes p100 precursors to p52 molecules, which translocate as active p52/RELB NF-κB heterodimers into the nucleus. HRS cells show constitutive activity of the classical and alternative NF-κB signaling pathway. This activity is probably mediated by diverse mechanisms, including receptor signaling through CD40, RANK, BCMA, and TACI; genomic REL and MAP3K14 (NIK) amplification; STAT STAT destructive mutations in the TNFAIP3, NFKBIA, and NFKBIE genes; and signaling through the EBV-encoded LMP1. The role of CD30 signaling in HRS cells is controversially discussed. HRS cells may also harbor nuclear BCL3/(p50)2 complexes, and in a few cases, the strong BCL3 expression appears to be mediated by genomic gains or chromosomal translocations. The JAK/STAT pathway is the main signaling pathway for cytokines. Upon binding of cytokines to their receptors, members of the JAK kinase family become activated by phosphorylation. The activated JAKs then phosphorylate and thereby activate STAT transcription factors. These phosphorylated factors homo- or heterodimerize and translocate into the nucleus where they activate target genes. Main inhibitors of the JAK/STAT pathway are the phosphatase PTPN1 and SOCS (suppressor of cytokine signaling) factors, which function by binding to JAK molecules and inhibiting their enzymatic activity and additionally by inducing proteasomal JAK degradation. In HRS cells, STAT3, 5, and 6 are constitutively active. Besides activation of cytokine receptors (e.g., IL13 receptor and IL21 receptor) through cytokines, activation of this pathway is mediated by genomic gains or rare translocations of the JAK2 gene, activating mutations in the STAT6 gene, and frequent inactivating mutations in the SOCS1 and PTPN1 gene. The frequency of genetic lesions and viral infections affecting NF-κB or STAT activity in cHL cases is indicated 3 Pathology and Molecular Pathology of Hodgkin Lymphoma Nearly 70% of EBV– cases carried TNFAIP3 mutations, indicating that EBV infection and A20 inactivation are alternative pathogenetic mechanisms in HL [88, 89]. As LMP1 of EBV, which is expressed in EBV-positive HRS cells, mimics an active CD40 receptor and signals through NF-κB [90, 91], LMP1 may replace the role of A20 inactivation in EBV+ HL. As it was recently revealed that also the LP cells of LPHL show strong constitutive NF-κB activity [37], also these cells were studied for mutations in NFKBIA and TNFAIP3, but clonal destructive mutations were not found (Table 3.1) [92]. Genetic lesions were also found in members of the JAK/STAT pathway, which is constitutively activated in HRS and LP cells. In about 40% of cases analyzed, both HRS and LP cells showed somatic mutations in the SOCS1 gene, which encodes a main inhibitor of STAT signaling (Fig. 3.3) [93, 94]. In HRS cells, recurrent mutations were additionally found in the gene of another negative regulator of JAK/STAT signaling, namely, the PTPN1 gene, which encodes a phosphatase [95]. Furthermore, a fraction of cHL cases show genomic gains or amplifications of the JAK2 locus, which encodes one of the kinases activating the STAT factors (Table 3.1) [82, 96]. Importantly, the genomic gains at 9p24 do not only affect the JAK2 locus, but additionally the PD-L1, PD-L2, and JMJD2C genes [97, 98]. PD-L1 and PD-L2 are inhibitory receptors for PD1-positive T cells and may hence inhibit a cytotoxic T cell attack on HRS cells. JMJD2C encodes a histone demethylase and plays a role in the epigenetic remodeling of HRS cells. Finally, the JAK2 gene is in rare instances also deregulated by chromosomal translocations [99]. Activating point mutations in the STAT6 gene and genomic gains involving this gene were also detected in HRS cells [10, 100]. Thus, multiple types of genetic lesions cause a constitutive JAK/ STAT signaling, suggesting an essential role of its deregulated activity for cHL pathogenesis. With the availability of high-throughput sequencing methods, tumor cells can now be studied for genetic lesions at a genome-wide level. An exome sequencing analysis of six cHL lines and the only LPHL cell line (DEV) revealed over 400 57 genes mutated in at least two of the lines [8]. This is a valuable database that should be considered when performing functional studies with these cell lines. A first whole exome sequencing study of primary HRS cells used flow-cytometry isolated lymphoma cell from ten cases of cHL [9]. Between 100 and 500 somatic mutations were found per case. A main finding of this analysis was recurrent inactivating mutations in the B2M gene. B2M is essential for MHC class I expression, so that the loss of its expression presumably leads to immune evasion from CD8+ cytotoxic T cells. Other novel recurrent mutations identified in that work affect several histone genes, the inositol-trisphosphate 3-kinase B (ITPKB), the B cell transcription factor EBF1, and the G protein subunit GNA13 [9]. Tiacci and colleagues performed a whole exome sequencing analysis of pools of HRS cells microdissected from 34 cases of cHL [10]. A median of 47 non-silent somatic mutations in the exomes was found. This study confirmed recurrent mutations in ITPKB and GNA13, and newly revealed recurrent point mutations in STAT6, further adding to the complexity of JAK/STAT deregulation in cHL. Although only four EBV+ cases were included in the study by Tiacci et al., it seems that such cases carry considerably fewer somatic mutations than the EBVnegative cases. A mutation study of LP cells of LPHL was based on a whole genome analysis of DLBCL clonally related to LPHL in the same patient, followed by targeted sequencing analysis of microdissected LP cells. In this work, three genes were found to be each mutated in about half of the cases of LPHL (also in cases without cooccurring DLBCL), namely, the genes encoding the kinase SGK1, the AP-1 family member JUNB, and the phosphatase DUSP2 [101]. 3.5 Deregulated Transcription Factor Networks and Signaling Pathways 3.5.1 The Lost B Cell Phenotype Early immunohistochemical studies already revealed that HRS cells usually do not express typical B cell markers, such as CD20, CD79b, or 58 the BCR [13, 102–104]. This lack of expression of B cell markers was indeed one of the reasons why the B cell origin of HRS cells was not revealed until genetic studies for Ig gene rearrangements unequivocally demonstrated a B cell identity of these cells (see above). Gene expression profiling studies of HRS cells in comparison to normal B cells then showed that there is a global loss of the B cell typical gene expression in HRS cells [105]. This downregulation involved all types of genes with important functions in these cells, for example, cell surface receptors (CD37, CD53), components of signaling pathways (SYK, BLK, SLP-65), and transcription factors (PU.B, A-MYB, SPI-B). As plasma cells also show a downregulation of many B cell- typical genes, it had been speculated that HRS cells lost their B cell gene expression and acquired a partial plasma cell differentiation program [2, 106]. However, a gene expression profiling study of microdissected HRS cells revealed that HRS cells have not acquired a plasma cell phenotype [107]. Remarkably, HRS cells have retained expression of molecules that are involved in antigen- presenting functions and the interaction with CD4+ T helper cells. HRS cells usually express CD40, CD80, and CD86 and often MHC class II [105, 108]. This indicates that an interaction with T helper cells is important for HRS cell survival. In line with this view, HRS cells are typically surrounded by CD40L expressing CD4+ T cells [109]. We are now beginning to understand which factors contribute to the lost B cell phenotype of HRS cells. First, several transcription factors that positively regulate the expression of multiple genes in B cells are downregulated, including OCT-2, PU.1, EBF1, ETS1, and BOB.1 [102, 103, 110–112]. The downregulation of ETS1 may often be due to heterozygous deletions of the gene, which have been observed in over 60% of cHL analyzed [112]. Second, although E2A, a master regulator of the B cell transcription program, is still expressed, HRS cells also show deregulated expression of ID2 and ABF1 [113– 115], which bind to E2A and inhibit its function [114]. The physiological role of ABF1 is poorly A. Rosenwald and R. Küppers understood, but ID2 is normally expressed in dendritic cells and natural killer cells, and supports the generation of these cells concomitant with suppression of B cell development [116, 117]. Third, HRS cells express activated NOTCH1, which normally induces T cell differentiation in lymphocyte precursors and suppresses a B lineage differentiation of such cells [118, 119]. Activation of NOTCH1 is probably caused by interaction with its ligand Jagged-1, which is expressed by other cells in the HL microenvironment [119], and by high-level expression of the NOTCH coactivator mastermind-like 2 (MAML2) [120]. Moreover, HRS cells have downregulated the NOTCH1 inhibitor Deltex1 [118]. Fourth, STAT5A and STAT5B are activated in HRS cells and have been reported to induce an HRS cell-like phenotype in normal B cells [121]. Constitutive active STAT5 induced expression of CD30 and of the T cell transcription factor GATA3 in the B cells and led to downregulation of BCR expression. Aberrant GATA3 expression in HRS cells is furthermore mediated by NOTCH1 and NF-κB activity in HRS cells [122]. Fifth, the downregulation of multiple B cell genes in HRS cells is further caused by epigenetic mechanisms, as DNA methylation has been detected for numerous such genes [123–125]. Sixth, HRS cells express several transcription factors that have important roles in hematopoietic stem cells and early lymphoid precursors, including GATA2, BMI1, RING1, and RYBP [126–129]. The expression of these factors may contribute to a “dedifferentiated” phenotype of HRS cells. Surprisingly, PAX5, the main B lineage commitment and maintenance factor, is still expressed in HRS cells, albeit at reduced levels [11]. As many of its direct target genes are not expressed, it is likely that PAX5 activity is inhibited. NOTCH1 is a candidate for this inhibition [118]. It may also be that PAX5 target genes are not expressed because other transcription factors needed for the efficient expression of these genes are missing. Expression of the myeloid specific colony- stimulating factor 1 receptor (CSF1R) by HRS cells is a further important example of aberrant 3 Pathology and Molecular Pathology of Hodgkin Lymphoma expression of a non-B cell gene in HRS cells [130]. CSF1R expression promotes HRS cell survival. The mechanism of its deregulated expression is remarkable, because this is mediated by derepression of an endogenous long terminal repeat upstream of the CSF1R gene that replaces the function of the normal CSF1R promoter [130]. The downregulation of many B cell transcription factors that also suppress the expression of non-B lineage genes, combined with the upregulated expression of genes promoting expression of genes of other hematopoietic cell types (e.g., NOTCH1, ID2), not only explains the lost B cell phenotype of HRS cells but also the heterogeneous expression of genes specifically expressed by dendritic cells, T cells, or other cell types. It is an intriguing question whether the lost B cell phenotype of HRS cells is related to their origin from crippled GC B cells. Perhaps, due to the stringent selection of B cells for expression of a functional BCR (a high-affinity one in the GC), there is a selection in HRS cell pathogenesis downregulating the B cell gene expression program to escape the selection forces that induce apoptosis in GC B cells with unfavorable IgV gene mutations. The observation that enforced re-expression of the B cell transcription factors PU.1, FOXO1, or E2A or the pharmacological restoration of the B cell phenotype in HL cell lines induces apoptosis is in line with this view [131–134]. However, the lost B cell phenotype could also be a side effect of so far unknown transforming events. 3.5.2 Constitutive Activation of Multiple Signaling Pathways It is obvious that tumor cells need to activate and deregulate signaling pathways and transcription factors that promote their survival and proliferation. Nevertheless, it is striking how many of such pathways are constitutively activated in HRS cells, and cHL appears to be rather unique among lymphoid malignancies in the extent to which multiple signaling pathways contribute to 59 the survival and expansion of HRS cells. It has already been mentioned above that HRS cells show constitutive NF-κB activity. This activity is essential for HRS cell survival [135] and is most likely not only mediated by genetic lesions (see above) but also by signaling through receptors. NF-κB factors of both the canonical pathway (p50/p65) and the noncanonical NF-κB pathway (p52/RelB) are activated (Fig. 3.3). HRS cells express the TNF receptor family members CD30, CD40, RANK, TACI, and BCMA, which activate NF-κB, and cells expressing the respective ligands are found in the HL microenvironment [109, 136–140]. There are, however, conflicting data about the role of CD30 in NF-κB activation [141, 142]. In EBV-positive cases of cHL, the virally encoded LMP1 mimics an active CD40 receptor and hence also contributes to NF-κB activation [143]. Another central signaling pathway, which is like NF-κB activated both by genetic lesions and by ligand-mediated receptor triggering, is the JAK/STAT pathway (Fig. 3.3). This is the main signaling pathway for cytokines. Activation of cytokine receptors causes activation of JAK kinases which in turn phosphorylate and thereby activate STAT transcription factors. The phosphorylated STAT factors dimerize and then translocate into the nucleus where they activate transcription of target genes. HRS cells show activation of STAT3, STAT5, and STAT6 [121, 144–146]. The activation of STAT6 is at least partly mediated by signaling through IL13. As HRS cells express IL13 and its receptor, STAT6 activation can be mediated through an autocrine stimulation loop [147, 148]. Signaling through the IL21 receptor contributes to STAT3 and STAT5 activation in HRS cells, which is also enhanced by the NF-κB activity in the cells [121, 149, 150]. As mentioned above, STAT5 activity may contribute to the lost B cell phenotype of HRS cells. Inhibition of STAT activity in HL cell lines resulted in reduced proliferation of the cells, further supporting an important pathogenetic role of this signaling pathway [144, 145, 147]. Receptor tyrosine kinases (RTKs) are important regulators of cell growth, survival, and proliferation. In multiple cancers, specific RTKs are 60 A. Rosenwald and R. Küppers activated, often by somatic mutations [151]. In toxic for these cells, revealing an essential role of contrast, HRS cells show multiple activated this factor in cHL pathophysiology [162]. RTKs, and their activation does not appear to be Finally, also the phosphatidylinositol 3-kinase due to activating mutations but at least partly to (PI3K)/AKT pathway, which is a main promoter ligand-mediated stimulation [152]. RTKs that are of cell survival, shows activity in HRS cells [164, often expressed in varying combinations in HRS 165]. AKT is a serine/threonine kinase that is cells include PDGFRA, DDR2, EPHB1, RON, activated in HRS cells, as evident from its phosTRKA, TRKB, CSF1R, and MET [130, 152, phorylated state and phosphorylation of known 153]. The expression of most of these is aberrant, target proteins [164, 165]. Inhibition of AKT in as they are not expressed by normal GC B cells HL cell lines causes cell death, suggesting an [130, 152]. They are also usually not expressed important role of active AKT in HRS cell surby other B cell non-HL, showing that this is a vival [164, 165]. PI3K may be activated in HRS specific feature of HL among B cell lymphomas cells by signaling through CD30, CD40, RANK, [152, 154]. Expression of multiple RTKs is most and RTK. Moreover, downregulation of the AKT pronounced in EBV-negative cases of cHL, sug- inhibitor INPP5D in HRS cells may further congesting that EBV activates pathways in HRS tribute to strong AKT activity in these cells [107]. cells replacing the function of RTKs [155]. For While we have a relatively detailed insight PDGFRA, TRKA, and CSF1R, a growth- into signaling pathways active in HRS cells, less inhibitory effect has been shown upon their inhi- is known about signaling pathways constitutively bition in HL cell lines, giving a first indication active in LP cells of LPHL. However, LP cells that the activity of RTKs is important for HRS also show a high constitutive activity of NF-κB cell proliferation [130, 152, 156]. [37]. RTKs are partly also aberrantly expressed Signaling through various receptors is medi- by these cells [152], and activation of the JAK/ ated by the mitogen-activated protein kinase STAT pathway has been observed [93]. (MAPK)/ERK pathway. In HRS cells, the serine/ In conclusion, HRS cells are characterized by threonine kinases ERK1, ERK2, and ERK5 are the deregulated and constitutive activation of activated [157, 158]. Inhibition of their activity multiple signaling pathways and transcription has antiproliferative effects on HL cell lines factors that contribute to the survival and prolif[158]. Signaling through CD30, CD40, and eration of these cells. The multitude of different RANK may contribute to the stimulation of this stimulated pathways appears to be rather unique pathway [158]. among human B cell lymphomas. Often, these The transcription factor AP-1 acts as homo- or pathways are activated by common mechanisms, heterodimers of JUN, FOS, and ATF compo- and they may interact in numerous ways. nents. In HRS cells, JUN and JUNB are overexpressed and constitutively active [159]. The overexpression of JUNB is mediated by NF-κB 3.6 Anti-apoptotic Mechanisms [159]. AP-1 induces many target genes and promotes proliferation of HRS cells. Target genes of With a presumed origin from pre-apoptotic GC B AP-1 include CD30 and galectin-1, the latter of cells, it is critical to understand through which which has immunomodulatory functions [160, mechanisms HRS cells escape from apoptosis. A 161]. HRS cells also show strong expression of number of factors contributing to HRS cell surBATF3, another member of the AP-1 transcrip- vival have already been discussed in the previous tion factor family [162, 163]. BATF3 expression section: constitutive activity of NF-κB, STAT, is induced by STAT3 and STAT6 in HRS cells. It PI3K, NOTCH1, AP-1, RTK, and ERK. Several forms heterodimers with JUN and JUNB, and the specific inhibitors of the two main apoptosis proto-oncogene MYC was identified as one of pathways deserve specific mentioning. Although the direct BATF3 target genes [162]. Importantly, HRS cells express the CD95 death receptor of downregulation of BATF3 in HL cell lines is the extrinsic apoptosis pathway as well as its 3 Pathology and Molecular Pathology of Hodgkin Lymphoma activating ligand, HL cell lines are resistant to CD95- mediated death induction, suggesting a specific inhibition of this pathway [166–168]. As mentioned above, this resistance is neither due to mutations in the CD95 receptor itself nor in its interaction partners FADD, caspase 8, or caspase 10. However, HRS cells show strong expression of the CD95 inhibitor CFLAR (previously known as cFLIP, cellular FADD-like interleukin 1b- converting enzyme-inhibitory protein), and this factor impairs CD95 signaling in HRS cells [166, 167]. Inhibition of the intrinsic (mitochondrial) apoptosis pathway is probably mediated through strong expression of the anti-apoptotic factors BCLXL and XIAP (X-linked inhibitor of apoptosis) and downregulation of the pro- apoptotic factor BIK [107, 169, 170]. BCLXL inhibits apoptosis at the level of the mitochondrial apoptosis induction, whereas XIAP inhibits activity of caspases 3 and 9, which are downstream executioners of the mitochondrial apoptosis program. Although HRS cells also express pro-apoptotic SMAC, which can inhibit XIAP, the cells show an impaired release of SMAC from the mitochondria into the cytoplasm [171]. As mentioned above, HRS cells express high levels of the pro-apoptotic TP53 factor, but resistance to TP53-mediated apoptosis appears to be rarely due to inactivating mutations in the TP53 gene. An important factor for the inhibition of TP53 activity is MDM2, which is expressed at high levels in HRS cells [172]. The functional role of MDM2 as a TP53 inhibitor in HRS cells is supported by the fact that HL cell lines expressing wild-type TP53 are rendered apoptosis- sensitive toward pharmacological apoptosis inducers upon inhibition of MDM2 by its antagonist nutlin 3 [173, 174]. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. References 13. 1. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H et al (2008) Classification of tumours of haematopoietic and lymphoid tissues, 4th edn. IARC Press, Lyon 2. Carbone A, Gloghini A, Gaidano G, Franceschi S, Capello D, Drexler HG et al (1998) Expression status of BCL-6 and syndecan-1 identifies distinct 14. 61 histogenetic subtypes of Hodgkin’s disease. Blood 92:2220–2228 Greiner A, Tobollik S, Buettner M, Jungnickel B, Herrmann K, Kremmer E et al (2005) Differential expression of activation-induced cytidine deaminase (AID) in nodular lymphocyte-predominant and classical Hodgkin lymphoma. J Pathol 205:541–547 Hartmann S, Eichenauer DA, Plutschow A, Mottok A, Bob R, Koch K et al (2013) The prognostic impact of variant histology in nodular lymphocyte- predominant Hodgkin lymphoma: a report from the German Hodgkin Study Group (GHSG). Blood 122:4246–4252 Hansmann ML, Fellbaum C, Hui PK, Zwingers T (1988) Correlation of content of B cells and Leu7- positive cells with subtype and stage in lymphocyte predominance type Hodgkin's disease. J Cancer Res Clin Oncol 114:405–410 Kamel OW, Gelb AB, Shibuya RB, Warnke RA (1993) Leu 7 (CD57) reactivity distinguishes nodular lymphocyte predominance Hodgkin's disease from nodular sclerosing Hodgkin's disease, T-cell- rich B-cell lymphoma and follicular lymphoma. Am J Pathol 142:541–546 Nam-Cha SH, Roncador G, Sanchez-Verde L, Montes-Moreno S, Acevedo A, Dominguez-Franjo P et al (2008) PD-1, a follicular T-cell marker useful for recognizing nodular lymphocyte-predominant Hodgkin lymphoma. Am J Surg Pathol 32:1252–1257 Liu Y, Abdul Razak FR, Terpstra M, Chan FC, Saber A, Nijland M et al (2014) The mutational landscape of Hodgkin lymphoma cell lines determined by wholeexome sequencing. Leukemia 28:2248–2251 Reichel J, Chadburn A, Rubinstein PG, Giulino- Roth L, Tam W, Liu Y et al (2015) Flow-sorting and exome sequencing reveals the oncogenome of primary Hodgkin and Reed-Sternberg cells. Blood 125:1061–1072 Tiacci E, Ladewig E, Schiavoni G, Penson A, Fortini E, Pettirossi V et al (2018) Pervasive mutations of JAK-STAT pathway genes in classical Hodgkin lymphoma. Blood 131:2454–2465 Foss HD, Reusch R, Demel G, Lenz G, Anagnostopoulos I, Hummel M et al (1999) Frequent expression of the B-cell-specific activator protein in Reed-Sternberg cells of classical Hodgkin’s disease provides further evidence for its B-cell origin. Blood 94:3108–3113 Korkolopoulou P, Cordell J, Jones M, Kaklamanis L, Tsenga A, Gatter KC et al (1994) The expression of the B-cell marker mb-1 (CD79a) in Hodgkin’s disease. Histopathology 24:511–515 Kuzu I, Delsol G, Jones M, Gatter KC, Mason DY (1993) Expression of the Ig-associated heterodimer (mb-1 and B29) in Hodgkin’s disease. Histopathology 22:141–144 Müschen M, Rajewsky K, Bräuninger A, Baur AS, Oudejans JJ, Roers A et al (2000) Rare occurrence of classical Hodgkin’s disease as a T cell lymphoma. J Exp Med 191:387–394 62 15. Seitz V, Hummel M, Marafioti T, Anagnostopoulos I, Assaf C, Stein H (2000) Detection of clonal T-cell receptor gamma-chain gene rearrangements in ReedSternberg cells of classic Hodgkin disease. Blood 95:3020–3024 16. Mani H, Jaffe ES (2009) Hodgkin lymphoma: an update on its biology with new insights into classification. Clin Lymphoma Myeloma 9:206–216 17. Traverse-Glehen A, Pittaluga S, Gaulard P, Sorbara L, Alonso MA, Raffeld M et al (2005) Mediastinal gray zone lymphoma: the missing link between classic Hodgkin’s lymphoma and mediastinal large B-cell lymphoma. Am J Surg Pathol 29:1411–1421 18. Eckerle S, Brune V, Döring C, Tiacci E, Bohle V, Sundstrom C et al (2009) Gene expression profiling of isolated tumour cells from anaplastic large cell lymphomas: insights into its cellular origin, pathogenesis and relation to Hodgkin lymphoma. Leukemia 23(11):2129–2138 19. Asano N, Yamamoto K, Tamaru J, Oyama T, Ishida F, Ohshima K et al (2009) Age-related Epstein-Barr virus (EBV)-associated B-cell lymphoproliferative disorders: comparison with EBV-positive classic Hodgkin lymphoma in elderly patients. Blood 113:2629–2636 20. Kanzler H, Küppers R, Hansmann ML, Rajewsky K (1996) Hodgkin and Reed-Sternberg cells in Hodgkin’s disease represent the outgrowth of a dominant tumor clone derived from (crippled) germinal center B cells. J Exp Med 184:1495–1505 21. Küppers R, Rajewsky K, Zhao M, Simons G, Laumann R, Fischer R et al (1994) Hodgkin disease: Hodgkin and Reed-Sternberg cells picked from histological sections show clonal immunoglobulin gene rearrangements and appear to be derived from B cells at various stages of development. Proc Natl Acad Sci U S A 91:10962–10966 22. Marafioti T, Hummel M, Foss H-D, Laumen H, Korbjuhn P, Anagnostopoulos I et al (2000) Hodgkin and Reed-Sternberg cells represent an expansion of a single clone originating from a germinal center B-cell with functional immunoglobulin gene rearrangements but defective immunoglobulin transcription. Blood 95:1443–1450 23. Müschen M, Küppers R, Spieker T, Bräuninger A, Rajewsky K, Hansmann ML (2001) Molecular single- cell analysis of Hodgkin- and Reed-Sternberg cells harboring unmutated immunoglobulin variable region genes. Lab Invest 81:289–295 24. Küppers R, Zhao M, Hansmann ML, Rajewsky K (1993) Tracing B cell development in human germinal centres by molecular analysis of single cells picked from histological sections. EMBO J 12:4955–4967 25. Küppers R, Rajewsky K (1998) The origin of Hodgkin and Reed/Sternberg cells in Hodgkin’s disease. Annu Rev Immunol 16:471–493 26. Lebecque S, de Bouteiller O, Arpin C, Banchereau J, Liu YJ (1997) Germinal center founder cells display propensity for apoptosis before onset of somatic mutation. J Exp Med 185:563–571 A. Rosenwald and R. Küppers 27. Bräuninger A, Hansmann ML, Strickler JG, Dummer R, Burg G, Rajewsky K et al (1999) Identification of common germinal-center B-cell precursors in two patients with both Hodgkin’s disease and Non- Hodgkin’s lymphoma. N Engl J Med 340:1239–1247 28. Küppers R, Sousa AB, Baur AS, Strickler JG, Rajewsky K, Hansmann ML (2001) Common germinal-center B-cell origin of the malignant cells in two composite lymphomas, involving classical Hodgkin's disease and either follicular lymphoma or B-CLL. Mol Med 7:285–292 29. Marafioti T, Hummel M, Anagnostopoulos I, Foss HD, Huhn D, Stein H (1999) Classical Hodgkin's disease and follicular lymphoma originating from the same germinal center B cell. J Clin Oncol 17:3804–3809 30. Küppers R, Dührsen U, Hansmann ML (2014) Pathogenesis, diagnosis, and treatment of composite lymphomas. Lancet Oncol 15:e435–e446 31. Weniger MA, Tiacci E, Schneider S, Arnolds J, Rüschenbaum S, Duppach J et al (2018) Human CD30+ B cells represent a unique subset related to Hodgkin lymphoma cells. J Clin Invest 128:2996–3007 32. Montes-Moreno S, Roncador G, Maestre L, Martinez N, Sanchez-Verde L, Camacho FI et al (2008) Gcet1 (centerin), a highly restricted marker for a subset of germinal center-derived lymphomas. Blood 111:351–358 33. Natkunam Y, Lossos IS, Taidi B, Zhao S, Lu X, Ding F et al (2005) Expression of the human germinal center-associated lymphoma (HGAL) protein, a new marker of germinal center B-cell derivation. Blood 105:3979–3986 34. Braeuninger A, Küppers R, Strickler JG, Wacker HH, Rajewsky K, Hansmann ML (1997) Hodgkin and Reed-Sternberg cells in lymphocyte predominant Hodgkin disease represent clonal populations of germinal center-derived tumor B cells. Proc Natl Acad Sci U S A 94:9337–9342 35. Marafioti T, Hummel M, Anagnostopoulos I, Foss HD, Falini B, Delsol G et al (1997) Origin of nodular lymphocyte-predominant Hodgkin's disease from a clonal expansion of highly mutated germinal-center B cells. N Engl J Med 337:453–458 36. Ohno T, Stribley JA, Wu G, Hinrichs SH, Weisenburger DD, Chan WC (1997) Clonality in nodular lymphocyte-predominant Hodgkin’s disease. N Engl J Med 337:459–465 37. Brune V, Tiacci E, Pfeil I, Döring C, Eckerle S, van Noesel CJM et al (2008) Origin and pathogenesis of nodular lymphocyte-predominant Hodgkin lymphoma as revealed by global gene expression analysis. J Exp Med 205:2251–2268 38. Küppers R, Bräuninger A, Müschen M, Distler V, Hansmann ML, Rajewsky K (2001) Evidence that Hodgkin and Reed-Sternberg cells in Hodgkin disease do not represent cell fusions. Blood 97:818–821 39. Drexler HG, Gignac SM, Hoffbrand AV, Minowada J (1989) Formation of multinucleated cells in a Hodgkin’s-disease-derived cell line. Int J Cancer 43:1083–1090 3 Pathology and Molecular Pathology of Hodgkin Lymphoma 40. Newcom SR, Kadin ME, Phillips C (1988) L-428 Reed-Sternberg cells and mononuclear Hodgkin's cells arise from a single cloned mononuclear cell. Int J Cell Cloning 6:417–431 41. Ikeda J, Mamat S, Tian T, Wang Y, Rahadiani N, Aozasa K et al (2010) Tumorigenic potential of mononucleated small cells of Hodgkin lymphoma cell lines. Am J Pathol 177:3081–3088 42. Rengstl B, Newrzela S, Heinrich T, Weiser C, Thalheimer FB, Schmid F et al (2013) Incomplete cytokinesis and re-fusion of small mononucleated Hodgkin cells lead to giant multinucleated Reed-Sternberg cells. Proc Natl Acad Sci U S A 110:20729–20734 43. Xavier de Carvalho A, Maiato H, Maia AF, Ribeiro SA, Pontes P, Bickmore W et al (2015) Reed- Sternberg cells form by abscission failure in the presence of functional Aurora B kinase. PLoS One 10:e0124629 44. Nakashima M, Ishii Y, Watanabe M, Togano T, Umezawa K, Higashihara M et al (2010) The side population, as a precursor of Hodgkin and Reed- Sternberg cells and a target for nuclear factor-kappaB inhibitors in Hodgkin’s lymphoma. Cancer Sci 101:2490–2496 45. Shafer JA, Cruz CR, Leen AM, Ku S, Lu A, Rousseau A et al (2010) Antigen-specific cytotoxic T lymphocytes can target chemoresistant side-population tumor cells in Hodgkin lymphoma. Leuk Lymphoma 51:870–880 46. Jansen MP, Hopman AH, Bot FJ, Haesevoets A, Stevens-Kroef MJ, Arends JW et al (1999) Morphologically normal, CD30-negative B-lymphocytes with chromosome aberrations in classical Hodgkin’s disease: the progenitor cell of the malignant clone? J Pathol 189:527–532 47. Spieker T, Kurth J, Küppers R, Rajewsky K, Bräuninger A, Hansmann ML (2000) Molecular single-cell analysis of the clonal relationship of small Epstein-Barr virus-infected cells and Epstein- Barr virus-harboring Hodgkin and Reed/Sternberg cells in Hodgkin disease. Blood 96:3133–3138 48. Jones RJ, Gocke CD, Kasamon YL, Miller CB, Perkins B, Barber JP et al (2009) Circulating clonotypic B cells in classic Hodgkin lymphoma. Blood 113:5920–5926 49. Küppers R (2009) Clonogenic B cells in classic Hodgkin lymphoma. Blood 114:3970–3971 50. Vockerodt M, Soares M, Kanzler H, Küppers R, Kube D, Hansmann ML et al (1998) Detection of clonal Hodgkin and Reed-Sternberg cells with identical somatically mutated and rearranged VH genes in different biopsies in relapsed Hodgkin’s disease. Blood 92:2899–2907 51. Weber-Matthiesen K, Deerberg J, Poetsch M, Grote W, Schlegelberger B (1995) Numerical chromosome aberrations are present within the CD30+ Hodgkin and Reed-Sternberg cells in 100% of analyzed cases of Hodgkin’s disease. Blood 86:1464–1468 63 52. Martin-Subero JI, Klapper W, Sotnikova A, CalletBauchu E, Harder L, Bastard C et al (2006) Chromosomal breakpoints affecting immunoglobulin loci are recurrent in Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma. Cancer Res 66:10332–10338 53. Szymanowska N, Klapper W, Gesk S, Küppers R, Martin-Subero JI, Siebert R (2008) BCL2 and BCL3 are recurrent translocation partners of the IGH locus. Cancer Genet Cytogenet 186:110–114 54. Gravel S, Delsol G, Al Saati T (1998) Single-cell analysis of the t(14;18)(q32;p21) chromosomal translocation in Hodgkin's disease demonstrates the absence of this transformation in neoplastic Hodgkin and Reed-Sternberg cells. Blood 91: 2866–2874 55. Poppema S, Kaleta J, Hepperle B (1992) Chromosomal abnormalities in patients with Hodgkin's disease: evidence for frequent involvement of the 14q chromosomal region but infrequent bcl-2 gene rearrangement in Reed-Sternberg cells. J Natl Cancer Inst 84:1789–1793 56. Steidl C, Shah SP, Woolcock BW, Rui L, Kawahara M, Farinha P et al (2011) MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers. Nature 471:377–381 57. Renné C, Martin-Subero JI, Hansmann ML, Siebert R (2005) Molecular cytogenetic analyses of immunoglobulin loci in nodular lymphocyte predominant Hodgkin’s lymphoma reveal a recurrent IGH-BCL6 juxtaposition. J Mol Diagn 7:352–356 58. Wlodarska I, Nooyen P, Maes B, Martin-Subero JI, Siebert R, Pauwels P et al (2003) Frequent occurrence of BCL6 rearrangements in nodular lymphocyte predominance Hodgkin lymphoma but not in classical Hodgkin lymphoma. Blood 101:706–710 59. Wlodarska I, Stul M, De Wolf-Peeters C, Hagemeijer A (2004) Heterogeneity of BCL6 rearrangements in nodular lymphocyte predominant Hodgkin’s lymphoma. Haematologica 89:965–972 60. Maggio EM, van den Berg A, de Jong D, Diepstra A, Poppema S (2003) Low frequency of FAS mutations in Reed-Sternberg cells of Hodgkin’s lymphoma. Am J Pathol 162:29–35 61. Müschen M, Re D, Bräuninger A, Wolf J, Hansmann ML, Diehl V et al (2000) Somatic mutations of the CD95 gene in Hodgkin and Reed-Sternberg cells. Cancer Res 60:5640–5643 62. Thomas RK, Schmitz R, Harttrampf AC, Abdil-Hadi A, Wickenhauser C, Distler V et al (2005) Apoptosis- resistant phenotype of classical Hodgkin’s lymphoma is not mediated by somatic mutations within genes encoding members of the death-inducing signaling complex (DISC). Leukemia 19:1079–1082 63. Bose S, Starczynski J, Chukwuma M, Baumforth K, Wei W, Morgan S et al (2007) Down-regulation of ATM protein in HRS cells of nodular sclerosis Hodgkin’s lymphoma in children occurs in the absence of ATM gene inactivation. J Pathol 213:329–336 64 64. Lespinet V, Terraz F, Recher C, Campo E, Hall J, Delsol G et al (2005) Single-cell analysis of loss of heterozygosity at the ATM gene locus in Hodgkin and Reed-Sternberg cells of Hodgkin’s lymphoma: ATM loss of heterozygosity is a rare event. Int J Cancer 114:909–916 65. Schmitz R, Thomas RK, Harttrampf AC, Wickenhauser C, Schultze JL, Hansmann ML et al (2006) The major subtypes of human B-cell lymphomas lack mutations in BCL-2 family member BAD. Int J Cancer 119:1738–1740 66. Maggio EM, Stekelenburg E, Van den Berg A, Poppema S (2001) TP53 gene mutations in Hodgkin lymphoma are infrequent and not associated with absence of Epstein-Barr virus. Int J Cancer 94:60–66 67. Montesinos-Rongen M, Roers A, Küppers R, Rajewsky K, Hansmann M-L (1999) Mutation of the p53 gene is not a typical feature of Hodgkin and Reed-Sternberg cells in Hodgkin’s disease. Blood 94:1755–1760 68. Feuerborn A, Moritz C, Von Bonin F, Dobbelstein M, Trümper L, Sturzenhofecker B et al (2006) Dysfunctional p53 deletion mutants in cell lines derived from Hodgkin’s lymphoma. Leuk Lymphoma 47:1932–1940 69. Küpper M, Joos S, Von Bonin F, Daus H, Pfreundschuh M, Lichter P et al (2001) MDM2 gene amplification and lack of p53 point mutations in Hodgkin and ReedSternberg cells: results from single-cell polymerase chain reaction and molecular cytogenetic studies. Br J Haematol 112:768–775 70. Jardin F, Pujals A, Pelletier L, Bohers E, Camus V, Mareschal S et al (2016) Recurrent mutations of the exportin 1 gene (XPO1) and their impact on selective inhibitor of nuclear export compounds sensitivity in primary mediastinal B-cell lymphoma. Am J Hematol 91:923–930 71. Abdul Razak FR, Diepstra A, Visser L, van den Berg A (2016) CD58 mutations are common in Hodgkin lymphoma cell lines and loss of CD58 expression in tumor cells occurs in Hodgkin lymphoma patients who relapse. Genes Immun 17:363–366 72. Schneider M, Schneider S, Zühlke-Jenisch R, Klapper W, Sundström C, Hartmann S et al (2015) Alterations of the CD58 gene in classical Hodgkin lymphoma. Genes Chromosomes Cancer 54:638–645 73. Cabannes E, Khan G, Aillet F, Jarrett RF, Hay RT (1999) Mutations in the IκΒα gene in Hodgkin’s disease suggest a tumour suppressor role for IκΒα. Oncogene 18:3063–3070 74. Emmerich F, Meiser M, Hummel M, Demel G, Foss HD, Jundt F et al (1999) Overexpression of I kappa B alpha without inhibition of NF-kappaB activity and mutations in the I kappa B alpha gene in Reed- Sternberg cells. Blood 94:3129–3134 75. Jungnickel B, Staratschek-Jox A, Bräuninger A, Spieker T, Wolf J, Diehl V et al (2000) Clonal deleterious mutations in the IkBa gene in the malignant cells in Hodgkin’s disease. J Exp Med 191:395–401 A. Rosenwald and R. Küppers 76. Lake A, Shield LA, Cordano P, Chui DT, Osborne J, Crae S et al (2009) Mutations of NFKBIA, encoding IkappaBalpha, are a recurrent finding in classical Hodgkin lymphoma but are not a unifying feature of non-EBV-associated cases. Int J Cancer 125:1334–1342 77. Emmerich F, Theurich S, Hummel M, Haeffker A, Vry MS, Döhner K et al (2003) Inactivating I kappa B epsilon mutations in Hodgkin/Reed-Sternberg cells. J Pathol 201:413–420 78. Mansouri L, Noerenberg D, Young E, Mylonas E, Abdulla M, Frick M et al (2016) Frequent NFKBIE deletions are associated with poor outcome in primary mediastinal B-cell lymphoma. Blood 128:2666–2670 79. Otto C, Giefing M, Massow A, Vater I, Gesk S, Schlesner M et al (2012) Genetic lesions of the TRAF3 and MAP3K14 genes in classical Hodgkin lymphoma. Br J Haematol 157:702–708 80. Schmidt A, Schmitz R, Giefing M, Martin-Subero JI, Gesk S, Vater I et al (2010) Rare occurrence of biallelic CYLD gene mutations in classical Hodgkin lymphoma. Genes Chromosomes Cancer 49: 803–809 81. Joos S, Granzow M, Holtgreve-Grez H, Siebert R, Harder L, Martin-Subero JI et al (2003) Hodgkin's lymphoma cell lines are characterized by frequent aberrations on chromosomes 2p and 9p including REL and JAK2. Int J Cancer 103:489–495 82. Joos S, Menz CK, Wrobel G, Siebert R, Gesk S, Ohl S et al (2002) Classical Hodgkin lymphoma is characterized by recurrent copy number gains of the short arm of chromosome 2. Blood 99:1381–1387 83. Martin-Subero JI, Gesk S, Harder L, Sonoki T, Tucker PW, Schlegelberger B et al (2002) Recurrent involvement of the REL and BCL11A loci in classical Hodgkin lymphoma. Blood 99:1474–1477 84. Barth TF, Martin-Subero JI, Joos S, Menz CK, Hasel C, Mechtersheimer G et al (2003) Gains of 2p involving the REL locus correlate with nuclear c-Rel protein accumulation in neoplastic cells of classical Hodgkin lymphoma. Blood 101:3681–3686 85. Steidl C, Telenius A, Shah SP, Farinha P, Barclay L, Boyle M et al (2010) Genome-wide copy number analysis of Hodgkin Reed-Sternberg cells identifies recurrent imbalances with correlations to treatment outcome. Blood 116:418–427 86. Martin-Subero JI, Wlodarska I, Bastard C, Picquenot JM, Höppner J, Giefing M et al (2006) Chromosomal rearrangements involving the BCL3 locus are recurrent in classical Hodgkin and peripheral T-cell lymphoma. Blood 108:401–402 87. Mathas S, Jöhrens K, Joos S, Lietz A, Hummel F, Janz M et al (2005) Elevated NF-kappaB p50 complex formation and Bcl-3 expression in classical Hodgkin, anaplastic large-cell, and other peripheral T-cell lymphomas. Blood 106:4287–4293 88. Kato M, Sanada M, Kato I, Sato Y, Takita J, Takeuchi K et al (2009) Frequent inactivation of A20 in B-cell lymphomas. Nature 459:712–716 3 Pathology and Molecular Pathology of Hodgkin Lymphoma 89. Schmitz R, Hartmann S, Giefing M, Mechtersheimer G, Zuhlke-Jenisch R, Martin-Subero JI et al (2007) Inactivating mutations of TNFAIP3 (A20) indicate a tumor suppressor role for A20 in Hodgkin's lymphoma and primary mediastinal B cell lymphoma. Haeamtologica. Hematol J 92 (Suppl. 5):41 90. Mosialos G, Birkenbach M, Yalamanchili R, VanArsdale T, Ware C, Kieff E (1995) The Epstein- Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family. Cell 80:389–399 91. Uchida J, Yasui T, Takaoka-Shichijo Y, Muraoka M, Kulwichit W, Raab-Traub N et al (1999) Mimicry of CD40 signals by Epstein-Barr virus LMP1 in B lymphocyte responses. Science 286:300–303 92. Schumacher MA, Schmitz R, Brune V, Tiacci E, Döring C, Hansmann ML et al (2010) Mutations in the genes coding for the NF-kappaB regulating factors IkappaBalpha and A20 are uncommon in nodular lymphocyte-predominant Hodgkin’s lymphoma. Haematologica 95:153–157 93. Mottok A, Renné C, Willenbrock K, Hansmann ML, Bräuninger A (2007) Somatic hypermutation of SOCS1 in lymphocyte-predominant Hodgkin lymphoma is accompanied by high JAK2 expression and activation of STAT6. Blood 110:3387–3390 94. Weniger MA, Melzner I, Menz CK, Wegener S, Bucur AJ, Dorsch K et al (2006) Mutations of the tumor suppressor gene SOCS-1 in classical Hodgkin lymphoma are frequent and associated with nuclear phospho-STAT5 accumulation. Oncogene 25:2679–2684 95. Gunawardana J, Chan FC, Telenius A, Woolcock B, Kridel R, Tan KL et al (2014) Recurrent somatic mutations of PTPN1 in primary mediastinal B cell lymphoma and Hodgkin lymphoma. Nat Genet 46:329–335 96. Joos S, Küpper M, Ohl S, von Bonin F, Mechtersheimer G, Bentz M et al (2000) Genomic imbalances including amplification of the tyrosine kinase gene JAK2 in CD30+ Hodgkin cells. Cancer Res 60:549–552 97. Green MR, Monti S, Rodig SJ, Juszczynski P, Currie T, O'Donnell E et al (2010) Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood 116:3268–3277 98. Rui L, Emre NC, Kruhlak MJ, Chung HJ, Steidl C, Slack G et al (2010) Cooperative epigenetic modulation by cancer amplicon genes. Cancer Cell 18:590–605 99. Van Roosbroeck K, Cox L, Tousseyn T, Lahortiga I, Gielen O, Cauwelier B et al (2011) JAK2 rearrangements, including the novel SEC31A-JAK2 fusion, are recurrent in classical Hodgkin lymphoma. Blood 117:4056–4064 65 100. Hartmann S, Martin-Subero JI, Gesk S, Husken J, Giefing M, Nagel I et al (2008) Detection of genomic imbalances in microdissected Hodgkin and Reed- Sternberg cells of classical Hodgkin's lymphoma by array-based comparative genomic hybridization. Haematologica 93:1318–1326 101. Hartmann S, Schuhmacher B, Rausch T, Fuller L, Döring C, Weniger M et al (2016) Highly recurrent mutations of SGK1, DUSP2 and JUNB in nodular lymphocyte predominant Hodgkin lymphoma. Leukemia 30:844–853 102. Re D, Müschen M, Ahmadi T, Wickenhauser C, Staratschek-Jox A, Holtick U et al (2001) Oct-2 and Bob-1 deficiency in Hodgkin and Reed Sternberg cells. Cancer Res 61:2080–2084 103. Stein H, Marafioti T, Foss HD, Laumen H, Hummel M, Anagnostopoulos I et al (2001) Down-regulation of BOB.1/OBF.1 and Oct2 in classical Hodgkin disease but not in lymphocyte predominant Hodgkin disease correlates with immunoglobulin transcription. Blood 97:496–501 104. Watanabe K, Yamashita Y, Nakayama A, Hasegawa Y, Kojima H, Nagasawa T et al (2000) Varied B-cell immunophenotypes of Hodgkin/Reed-Sternberg cells in classic Hodgkin’s disease. Histopathology 36:353–361 105. Schwering I, Bräuninger A, Klein U, Jungnickel B, Tinguely M, Diehl V et al (2003) Loss of the B-lineage-specific gene expression program in Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma. Blood 101:1505–1512 106. Carbone A, Gloghini A, Larocca LM, Antinori A, Falini B, Tirelli U et al (1999) Human immunodeficiency virus-associated Hodgkin’s disease derives from post-germinal center B cells. Blood 93:2319–2326 107. Tiacci E, Döring C, Brune V, van Noesel CJ, Klapper W, Mechtersheimer G et al (2012) Analyzing primary Hodgkin and Reed-Sternberg cells to capture the molecular and cellular pathogenesis of classical Hodgkin lymphoma. Blood 120:4609–4620 108. Poppema S (1996) Immunology of Hodgkin’s disease. Baillieres Clin Haematol 9:447–457 109. Carbone A, Gloghini A, Gruss HJ, Pinto A (1995) CD40 ligand is constitutively expressed in a subset of T cell lymphomas and on the microenvironmental reactive T cells of follicular lymphomas and Hodgkin’s disease. Am J Pathol 147:912–922 110. Torlakovic E, Tierens A, Dang HD, Delabie J (2001) The transcription factor PU.1, necessary for B-cell development is expressed in lymphocyte predominance, but not classical Hodgkin’s disease. Am J Pathol 159:1807–1814 111. Bohle V, Döring C, Hansmann ML, Küppers R (2013) Role of early B-cell factor 1 (EBF1) in Hodgkin lymphoma. Leukemia 27:671–679 112. Overbeck BM, Martin-Subero JI, Ammerpohl O, Klapper W, Siebert R, Giefing M (2012) ETS1 encoding a transcription factor involved in B-cell A. Rosenwald and R. Küppers 66 113. 114. 115. 116. 117. 118. 119. 120. 121. 122. 123. 124. differentiation is recurrently deleted and downregulated in classical Hodgkin’s lymphoma. Haematologica 97:1612–1614 Küppers R, Klein U, Schwering I, Distler V, Bräuninger A, Cattoretti G et al (2003) Identification of Hodgkin and Reed-Sternberg cell-specific genes by gene expression profiling. J Clin Invest 111:529–537 Mathas S, Janz M, Hummel F, Hummel M, Wollert- Wulf B, Lusatis S et al (2006) Intrinsic inhibition of transcription factor E2A by HLH proteins ABF-1 and Id2 mediates reprogramming of neoplastic B cells in Hodgkin lymphoma. Nat Immunol 7:207–215 Renné C, Martin-Subero JI, Eickernjager M, Hansmann ML, Küppers R, Siebert R et al (2006) Aberrant expression of ID2, a suppressor of B-cell- specific gene expression, in Hodgkin’s lymphoma. Am J Pathol 169:655–664 Hacker C, Kirsch RD, Ju XS, Hieronymus T, Gust TC, Kuhl C et al (2003) Transcriptional profiling identifies Id2 function in dendritic cell development. Nat Immunol 4:380–386 Yokota Y, Mansouri A, Mori S, Sugawara S, Adachi S, Nishikawa S et al (1999) Development of peripheral lymphoid organs and natural killer cells depends on the helix-loop-helix inhibitor Id2. Nature 397:702–706 Jundt F, Acikgoz O, Kwon SH, Schwarzer R, Anagnostopoulos I, Wiesner B et al (2008) Aberrant expression of Notch1 interferes with the B-lymphoid phenotype of neoplastic B cells in classical Hodgkin lymphoma. Leukemia 22:1587–1594 Jundt F, Anagnostopoulos I, Förster R, Mathas S, Stein H, Dörken B (2002) Activated Notch 1 signaling promotes tumor cell proliferation and survival in Hodgkin and anaplastic large cell lymphoma. Blood 99:3398–3403 Köchert K, Ullrich K, Kreher S, Aster JC, Kitagawa M, Johrens K et al (2011) High-level expression of Mastermind-like 2 contributes to aberrant activation of the NOTCH signaling pathway in human lymphomas. Oncogene 30(15):1831–1840 Scheeren FA, Diehl SA, Smit LA, Beaumont T, Naspetti M, Bende RJ et al (2008) IL-21 is expressed in Hodgkin lymphoma and activates STAT5; evidence that activated STAT5 is required for Hodgkin lymphomagenesis. Blood 111:4706–4715 Stanelle J, Döring C, Hansmann ML, Küppers R (2010) Mechanisms of aberrant GATA3 expression in classical Hodgkin lymphoma and its consequences for the cytokine profile of Hodgkin and Reed/Sternberg cells. Blood 116:4202–4211 Doerr JR, Malone CS, Fike FM, Gordon MS, Soghomonian SV, Thomas RK et al (2005) Patterned CpG methylation of silenced B cell gene promoters in classical Hodgkin lymphoma-derived and primary effusion lymphoma cell lines. J Mol Biol 350:631–640 Ushmorov A, Leithäuser F, Sakk O, Weinhausel A, Popov SW, Möller P et al (2006) Epigenetic 125. 126. 127. 128. 129. 130. 131. 132. 133. 134. 135. 136. 137. processes play a major role in B-cell-specific gene silencing in classical Hodgkin lymphoma. Blood 107:2493–2500 Ammerpohl O, Haake A, Pellissery S, Giefing M, Richter J, Balint B et al (2012) Array-based DNA methylation analysis in classical Hodgkin lymphoma reveals new insights into the mechanisms underlying silencing of B cell-specific genes. Leukemia 26:185–188 Dukers DF, van Galen JC, Giroth C, Jansen P, Sewalt RG, Otte AP et al (2004) Unique polycomb gene expression pattern in Hodgkin's lymphoma and Hodgkin’s lymphoma-derived cell lines. Am J Pathol 164:873–881 Raaphorst FM, van Kemenade FJ, Blokzijl T, Fieret E, Hamer KM, Satijn DP et al (2000) Coexpression of BMI-1 and EZH2 polycomb group genes in Reed- Sternberg cells of Hodgkin’s disease. Am J Pathol 157:709–715 Sanchez-Beato M, Sanchez E, Garcia JF, Perez- Rosado A, Montoya MC, Fraga M et al (2004) Abnormal PcG protein expression in Hodgkin’s lymphoma. Relation with E2F6 and NFkappaB transcription factors. J Pathol 204:528–537 Schneider EM, Torlakovic E, Stuhler A, Diehl V, Tesch H, Giebel B (2004) The early transcription factor GATA-2 is expressed in classical Hodgkin’s lymphoma. J Pathol 204:538–545 Lamprecht B, Walter K, Kreher S, Kumar R, Hummel M, Lenze D et al (2010) Derepression of an endogenous long terminal repeat activates the CSF1R proto-oncogene in human lymphoma. Nat Med 16:571–579 Yuki H, Ueno S, Tatetsu H, Niiro H, Iino T, Endo S et al (2013) PU.1 is a potent tumor suppressor in classical Hodgkin lymphoma cells. Blood 121:962–970 Guan H, Xie L, Wirth T, Ushmorov A (2016) Repression of TCF3/E2A contributes to Hodgkin lymphomagenesis. Oncotarget 7:36854–36864 Xie L, Ushmorov A, Leithäuser F, Guan H, Steidl C, Farbinger J et al (2012) FOXO1 is a tumor suppressor in classical Hodgkin lymphoma. Blood 119:3503–3511 Du J, Neuenschwander M, Yu Y, Dabritz JH, Neuendorff NR, Schleich K et al (2017) Pharmacological restoration and therapeutic targeting of the B-cell phenotype in classical Hodgkin lymphoma. Blood 129:71–81 Bargou RC, Emmerich F, Krappmann D, Bommert K, Mapara MY, Arnold W et al (1997) Constitutive nuclear factor-kappaB-RelA activation is required for proliferation and survival of Hodgkin’s disease tumor cells. J Clin Invest 100:2961–2969 Carbone A, Gloghini A, Gattei V, Aldinucci D, Degan M, De Paoli P et al (1995) Expression of functional CD40 antigen on Reed-Sternberg cells and Hodgkin’s disease cell lines. Blood 85:780–789 Chiu A, Xu W, He B, Dillon SR, Gross JA, Sievers E et al (2007) Hodgkin lymphoma cells express TACI and BCMA receptors and generate survival 3 Pathology and Molecular Pathology of Hodgkin Lymphoma 138. 139. 140. 141. 142. 143. 144. 145. 146. 147. 148. 149. and proliferation signals in response to BAFF and APRIL. Blood 109:729–739 Fiumara P, Snell V, Li Y, Mukhopadhyay A, Younes M, Gillenwater AM et al (2001) Functional expression of receptor activator of nuclear factor kappaB in Hodgkin disease cell lines. Blood 98:2784–2790 Molin D, Fischer M, Xiang Z, Larsson U, Harvima I, Venge P et al (2001) Mast cells express functional CD30 ligand and are the predominant CD30L- positive cells in Hodgkin’s disease. Br J Haematol 114:616–623 Schwab U, Stein H, Gerdes J, Lemke H, Kirchner H, Schaadt M et al (1982) Production of a monoclonal antibody specific for Hodgkin and Sternberg-Reed cells of Hodgkin’s disease and a subset of normal lymphoid cells. Nature 299:65–67 Hirsch B, Hummel M, Bentink S, Fouladi F, Spang R, Zollinger R et al (2008) CD30-induced signaling is absent in Hodgkin’s cells but present in anaplastic large cell lymphoma cells. Am J Pathol 172: 510–520 Horie R, Watanabe T, Morishita Y, Ito K, Ishida T, Kanegae Y et al (2002) Ligand-independent signaling by overexpressed CD30 drives NF-kappaB activation in Hodgkin-Reed-Sternberg cells. Oncogene 21:2493–2503 Kilger E, Kieser A, Baumann M, Hammerschmidt W (1998) Epstein-Barr virus-mediated B-cell proliferation is dependent upon latent membrane protein 1, which simulates an activated CD40 receptor. EMBO J 17:1700–1709 Baus D, Pfitzner E (2006) Specific function of STAT3, SOCS1, and SOCS3 in the regulation of proliferation and survival of classical Hodgkin lymphoma cells. Int J Cancer 118:1404–1413 Kube D, Holtick U, Vockerodt M, Ahmadi T, Behrmann I, Heinrich PC et al (2001) STAT3 is constitutively activated in Hodgkin cell lines. Blood 98:762–770 Skinnider BF, Elia AJ, Gascoyne RD, Patterson B, Trümper L, Kapp U et al (2002) Signal transducer and activator of transcription 6 is frequently activated in Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma. Blood 99:618–626 Kapp U, Yeh WC, Patterson B, Elia AJ, Kagi D, Ho A et al (1999) Interleukin 13 is secreted by and stimulates the growth of Hodgkin and Reed-Sternberg cells. J Exp Med 189:1939–1946 Skinnider BF, Elia AJ, Gascoyne RD, Trumper LH, von Bonin F, Kapp U et al (2001) Interleukin 13 and interleukin 13 receptor are frequently expressed by Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma. Blood 97:250–255 Hinz M, Lemke P, Anagnostopoulos I, Hacker C, Krappmann D, Mathas S et al (2002) Nuclear factor kappaB-dependent gene expression profiling of Hodgkin's disease tumor cells, pathogenetic significance, and link to constitutive signal transducer and activator of transcription 5a activity. J Exp Med 196:605–617 67 150. Lamprecht B, Kreher S, Anagnostopoulos I, Johrens K, Monteleone G, Jundt F et al (2008) Aberrant expression of the Th2 cytokine IL-21 in Hodgkin lymphoma cells regulates STAT3 signaling and attracts Treg cells via regulation of MIP-3{alpha}. Blood 112:3339–3347 151. Blume-Jensen P, Hunter T (2001) Oncogenic kinase signalling. Nature 411:355–365 152. Renné C, Willenbrock K, Küppers R, Hansmann M-L, Bräuninger A (2005) Autocrine and paracrine activated receptor tyrosine kinases in classical Hodgkin lymphoma. Blood 105:4051–4059 153. Teofili L, Di Febo AL, Pierconti F, Maggiano N, Bendandi M, Rutella S et al (2001) Expression of the c-met proto-oncogene and its ligand, hepatocyte growth factor, in Hodgkin disease. Blood 97:1063–1069 154. Renné C, Willenbrock K, Martin-Subero JI, Hinsch N, Döring C, Tiacci E et al (2007) High expression of several tyrosine kinases and activation of the PI3K/ AKT pathway in mediastinal large B cell lymphoma reveals further similarities to Hodgkin lymphoma. Leukemia 21:780–787 155. Renné C, Hinsch N, Willenbrock K, Fuchs M, Klapper W, Engert A et al (2007) The aberrant coexpression of several receptor tyrosine kinases is largely restricted to EBV-negative cases of classical Hodgkin’s lymphoma. Int J Cancer 120:2504–2509 156. Renne C, Minner S, Küppers R, Hansmann ML, Bräuninger A (2008) Autocrine NGFbeta/TRKA signalling is an important survival factor for Hodgkin lymphoma derived cell lines. Leuk Res 32:163–167 157. Nagel S, Burek C, Venturini L, Scherr M, Quentmeier H, Meyer C et al (2007) Comprehensive analysis of homeobox genes in Hodgkin lymphoma cell lines identifies dysregulated expression of HOXB9 mediated via ERK5 signaling and BMI1. Blood 109:3015–3023 158. Zheng B, Fiumara P, Li YV, Georgakis G, Snell V, Younes M et al (2003) MEK/ERK pathway is aberrantly active in Hodgkin disease: a signaling pathway shared by CD30, CD40, and RANK that regulates cell proliferation and survival. Blood 102:1019–1027 159. Mathas S, Hinz M, Anagnostopoulos I, Krappmann D, Lietz A, Jundt F et al (2002) Aberrantly expressed c-Jun and JunB are a hallmark of Hodgkin lymphoma cells, stimulate proliferation and synergize with NF-kappa B. EMBO J 21:4104–4113 160. Juszczynski P, Ouyang J, Monti S, Rodig SJ, Takeyama K, Abramson J et al (2007) The AP1-dependent secretion of galectin-1 by Reed Sternberg cells fosters immune privilege in classical Hodgkin lymphoma. Proc Natl Acad Sci U S A 104:13134–13139 161. Watanabe M, Ogawa Y, Ito K, Higashihara M, Kadin ME, Abraham LJ et al (2003) AP-1 mediated relief of repressive activity of the CD30 promoter microsatellite in Hodgkin and Reed-Sternberg cells. Am J Pathol 163:633–641 68 162. Lollies A, Hartmann S, Schneider M, Bracht T, Weiss AL, Arnolds J et al (2018) An oncogenic axis of STAT-mediated BATF3 upregulation causing MYC activity in classical Hodgkin lymphoma and anaplastic large cell lymphoma. Leukemia 32:92–101 163. Vrzalikova K, Ibrahim M, Vockerodt M, Perry T, Margielewska S, Lupino L et al (2018) S1PR1 drives a feedforward signalling loop to regulate BATF3 and the transcriptional programme of Hodgkin lymphoma cells. Leukemia 32:214–223 164. Dutton A, Reynolds GM, Dawson CW, Young LS, Murray PG (2005) Constitutive activation of phosphatidyl-inositide 3 kinase contributes to the survival of Hodgkin's lymphoma cells through a mechanism involving Akt kinase and mTOR. J Pathol 205:498–506 165. Georgakis GV, Li Y, Rassidakis GZ, Medeiros LJ, Mills GB, Younes A (2006) Inhibition of the phosphatidylinositol- 3 kinase/Akt promotes G1 cell cycle arrest and apoptosis in Hodgkin lymphoma. Br J Haematol 132:503–511 166. Dutton A, O'Neil JD, Milner AE, Reynolds GM, Starczynski J, Crocker J et al (2004) Expression of the cellular FLICE-inhibitory protein (c-FLIP) protects Hodgkin’s lymphoma cells from autonomous Fas-mediated death. Proc Natl Acad Sci U S A 101:6611–6616 167. Mathas S, Lietz A, Anagnostopoulos I, Hummel F, Wiesner B, Janz M et al (2004) c-FLIP mediates resistance of Hodgkin/Reed-Sternberg cells to death receptor-induced apoptosis. J Exp Med 199:1041–1052 A. Rosenwald and R. Küppers 168. Re D, Hofmann A, Wolf J, Diehl V, Staratschek- Jox A (2000) Cultivated H-RS cells are resistant to CD95L-mediated apoptosis despite expression of wild-type CD95. Exp Hematol 28:31–35 169. Chu WS, Aguilera NS, Wei MQ, Abbondanzo SL (1999) Antiapoptotic marker Bcl-X(L), expression on Reed-Sternberg cells of Hodgkin’s disease using a novel monoclonal marker, YTH-2H12. Hum Pathol 30:1065–1070 170. Kashkar H, Haefs C, Shin H, Hamilton-Dutoit SJ, Salvesen GS, Krönke M et al (2003) XIAP-mediated caspase inhibition in Hodgkin’s lymphoma-derived B cells. J Exp Med 198:341–347 171. Kashkar H, Seeger JM, Hombach A, Deggerich A, Yazdanpanah B, Utermohlen O et al (2006) XIAP targeting sensitizes Hodgkin lymphoma cells for cytolytic T-cell attack. Blood 108:3434–3440 172. Sanchez-Beato M, Piris MA, Martinez-Montero JC, Garcia JF, Villuendas R, Garcia FJ et al (1996) MDM2 and p21WAF1/CIP1, wild-type p53-induced proteins, are regularly expressed by Sternberg-Reed cells in Hodgkin's disease. J Pathol 180:58–64 173. Drakos E, Thomaides A, Medeiros LJ, Li J, Leventaki V, Konopleva M et al (2007) Inhibition of p53-murine double minute 2 interaction by nutlin3A stabilizes p53 and induces cell cycle arrest and apoptosis in Hodgkin lymphoma. Clin Cancer Res 13:3380–3387 174. Janz M, Stuhmer T, Vassilev LT, Bargou RC (2007) Pharmacologic activation of p53-dependent and p53-independent apoptotic pathways in Hodgkin/ Reed-Sternberg cells. Leukemia 21:772–779 4 Microenvironment, Cross-Talk, and Immune Escape Mechanisms Lydia Visser, Johanna Veldman, Sibrand Poppema, Anke van den Berg, and Arjan Diepstra Contents 4.1 4.1.1 4.1.2 4.1.3 4.1.4 4.1.5 4.1.6 4.1.7 Microenvironment Hodgkin Lymphoma Subtypes Epstein-Barr Virus Human Immunodeficiency Virus T Cell Subsets in cHL T Cell Subsets in NLPHL Fibrosis and Sclerosis Eosinophils, Plasma Cells, Mast Cells, and B Cells 70 70 70 71 71 73 74 74 4.2 4.2.1 4.2.2 ross-Talk between HRS Cells and Microenvironment C Factors Supporting Tumor Growth Shaping the Environment 74 74 76 4.3 4.3.1 4.3.2 4.3.3 4.3.4 4.3.5 I mmune Escape Mechanisms Antigen Presentation HLA Class I Expression HLA Class II Expression Immune Checkpoints Immunosuppression 77 77 78 78 79 80 4.4 Prognostic Impact of the Microenvironment 81 4.5 Conclusion 81 References 81 L. Visser · J. Veldman · S. Poppema A. van den Berg · A. Diepstra (*) Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands e-mail: l.visser@umcg.nl; j.veldman@umcg.nl; s.poppema@rug.nl; a.van.den.berg01@umcg.nl; a.diepstra@umcg.nl © Springer Nature Switzerland AG 2020 A. Engert, A. Younes (eds.), Hodgkin Lymphoma, Hematologic Malignancies, https://doi.org/10.1007/978-3-030-32482-7_4 69 L. Visser et al. 70 4.1 Microenvironment 4.1.1 Hodgkin Lymphoma Subtypes When discussing the microenvironment in Hodgkin lymphoma (HL), it is important to recognize the different HL subtypes described by the WHO classification [1, 2]. The classical HL (cHL) subtypes are defined in large part by the composition of the reactive infiltrate (Table 4.1). The most prevalent subtype is the nodular sclerosis type that consists of a nodular background with thick fibrotic bands, usually with a thickened lymph node capsule. In addition to the lacunar type of Hodgkin/ReedSternberg (HRS) cells, there is a microenvironment consisting of T cells, eosinophils, and histiocytes, with a variable admixture of neutrophils, plasma cells, fibroblasts, and mast cells. The second most common subtype is mixed cellularity, which is defined by the presence of typical HRS cells and a diffuse infiltrate of T cells, eosinophils, histiocytes, and plasma cells, sometimes with the formation of granuloma-like clusters or granulomas (Fig. 4.1). Lymphocyte-rich cHL also comprises typical HRS cells in a nodular or diffuse microenvironment and small B and/or T lymphocytes dominating the background, sometimes with admixture of histiocytes. Granulocytes are not present in this subtype. The rare lymphocyte-depleted subtype harbors a high percentage of HRS cells in a background consisting of fibroblasts and a low number of T cells. Nodular lymphocyte predominance (NLP) HL is an entity that is fundamentally different from cHL. The morphology may closely resemble that of the nodular variant of the classical lymphocyterich subtype, both involving follicular areas with many small B cells, but NLPHL can also show other growth patterns [3]. The characteristics of the tumor cells and the T cells in NLPHL are different from cHL. HRS cells show a loss of B cell phenotype, while in NLPHL the lymphocyte-predominant (LP) tumor cells share many markers with germinal center B cells. The T cells in cHL have features of paracortical T cells, while those in NLPHL are similar to germinal center T cells (T follicular helper cells) [4–6]. 4.1.2 Epstein-Barr Virus The presence of latent Epstein-Barr virus (EBV) genomes in HRS cells appears to influence the composition of the microenvironment. Positive EBV status is strongly associated with the mixed Fig. 4.1 The microenvironment in mixed cellularity classical Hodgkin lymphoma. RS classical Reed-Sternberg cell, H mononuclear Hodgkin tumor cell, T T lymphocyte, Hi histiocyte, E eosinophil, P plasma cell. Hematoxylin and eosin staining Table 4.1 Composition of the microenvironment in different Hodgkin lymphoma (HL) subtypes Subtype Nodular sclerosis EBV (%) Background 10–40 Nodular + fibrosis T cells CD4 > CD8, Th2, Treg > Th1 Mixed cellularity 75 Diffuse Lymphocyte rich Lymphocyte depleted (including HIV+) Nodular lymphocyte predominant 40–80 80–100 Nodular or diffuse Diffuse CD4 > CD8, Th2, Treg > Th1 CD4 > CD8 – ~2 Nodular (+diffuse) Th2, PD1+/CD57+ Tfh, CD4+/8+ Other cells Eosinophils, histiocytes, fibroblasts, B cells, mast cells (neutrophils) Eosinophils, histiocytes, plasma cells, B cells Histiocytes Fibroblasts Histiocytes, B cells 4 Microenvironment, Cross-Talk, and Immune Escape Mechanisms cellularity subtype (~75% EBV-positive) and is almost always absent in NLPHL [7]. Depending on the geographic locale, EBV is present in the HRS cells in 10–40% in nodular sclerosis cases. The percentage of EBV-positive lymphocyte-rich cHL cases is not very clear, but is probably between 40% and 80%. EBV infects more than 90% of the world population and establishes a lifelong latent infection in B cells in its host. Potent cytotoxic immune responses keep the number of EBV-infected B cells at approximately 1/100,000 and usually prevents EBV-driven malignant transformation in immunocompetent individuals. Accordingly, EBV-positive cHL cases contain slightly more CD8+ cytotoxic T cells in the reactive background compared to EBV-negative cHL cases [8]. 4.1.3 Human Immunodeficiency Virus In patients with an impaired immune response, cHL occurs more frequently. After solid organ transplantation, there is a small increase in the incidence of cHL that can largely be attributed to EBV-positive cHL. Human immunodeficiency virus (HIV)-infected individuals have an approximate 10 times increased risk of developing cHL [9]. In comparison to non-HIV-associated cHL, these tumors are more often EBV-associated, mixed cellularity and lymphocyte depletion subtypes, and usually contain more tumor cells. This may reflect a functional defect in the immune response, in particular to EBV, presumably caused by the impairment of CD4+ T cells by HIV. On the other hand, the importance of CD4+ T cells for supporting the growth of HRS cells is also illustrated in HIV-positive patients, in which an increase in the incidence of HIV-associated cHL has been observed after introduction of highly active antiretroviral therapy (HAART) [10]. 4.1.4 T Cell Subsets in cHL A unifying feature of the reactive infiltrate in virtually all cHL subtypes is the presence of large 71 numbers of CD4+ T cells. Besides being widely distributed in the background, these CD4+ T cells form a tight rosette around the tumor cells. T cells within these rosettes often have a distinct phenotype, which is different from the phenotype of the T cells that are located further away from the cHL tumor cells (Fig. 4.2). In general, CD4+ T cells are divided into naive (CD45RA+) and memory (CD45RO+) subsets based on whether they have previously been stimulated by an antigen or not. A large subset of CD4+ T cells consists of the so-called helper T (Th) cells; these cells play an important role in helping other cells to induce an effective immune response. Th cells can be further divided into Th0 (naive), Th1 (cellular response), Th2 (humoral response), Th17 (IL-17 producing), and Treg (regulating responses of other cells) cells. The Treg cells can be further divided into Th3 (transforming growth factor-β (TGF-β) producing), Tr1 (IL-10 producing), and CD4+CD25+ Treg (originating from the thymus) subpopulations. Some, but not all, Treg cells express the transcription factor FoxP3. The T cells in cHL consist mainly of CD4+ T cells that have a memory phenotype (CD45RO+) and express several activation markers including CD28, CD38, CD69, CD71, CD25, and HLA-DR, as well as markers like CD28, CTLA-4, and CD40L. However, these T cells lack expression of CD26 [11]. This lack of CD26 expression is most striking in the areas surrounding the tumor cells. CD26, dipeptidyl peptidase IV, regulates proteolytic processing of several chemokines, e.g., CCL5 (Rantes), CCL11 (Eotaxin), and CCL22 (MDC) [12]. CD26 is also associated with adenosine deaminase (ADA) and CD45RO and when interacting with anti-CD26 antibodies leads to enhanced T cell activation through triggering of the T cell receptor [13]. CD26 is preferentially expressed on CD4+CD45RO+ cells and is normally upregulated after activation. However, CD26 cannot be upregulated by ex vivo activation of the CD26-negative cells from cHL lesions. In general, a high CD26 expression level correlates with a Th1 subtype. The transcription factor expression pattern indicates that the CD4+ T cells in cHL are predominantly Th2 (c-Maf) and Treg (FoxP3) [4, 14]. 72 L. Visser et al. Fig. 4.2 Shaping the microenvironment in classical Hodgkin lymphoma (HL). Immunohistochemistry of classical HL cases. In the upper panel left, strong and specific staining of Hodgkin/Reed-Sternberg (HRS) cells for chemokine CCL17 (TARC). This chemokine attracts CCR4+ lymphocytes (upper panel right). A large proportion of reactive T cells are Treg cells, as shown by positive staining for transcription factor FoxP3 (lower panel left) and activation marker CD25 (lower panel right) The CD4+CD26− T cell subset in cHL has reduced mRNA levels of Th1- and Th2-associated cytokines in comparison to the CD4+CD26+ T cells from cHL and CD4+ T cells (both CD26− and CD26+) in reactive lymph nodes [15]. Based on much higher mRNA expression levels of IL-2RA (CD25), CCR4, FoxP3, CTLA4, TNFRSF4 (OX-40), and TNFRSF18 (GITR) observed in the CD4+CD26− T cells from cHL, it has been postulated that these cells have a Treg phenotype (Fig. 4.2). In addition, mildly enhanced IL-17 levels can be observed both in CD4+CD26− and CD4+CD26+ T cells from cHL in comparison to the T cells from tonsil. Upon stimulation, the CD4+CD26− T cells fail to induce expression of cytokines, suggesting that the T cell population rosetting around the HRS cells or located in the direct vicinity of the HRS cells have an anergic phenotype (i.e., do not respond to stimulation) [15]. Immunohistochemistry for several Treg- associated molecules demonstrates that the rosetting T cells in cHL express GITR, CCR4, and CD25, but not FoxP3. Scattered FoxP3-positive cells are present in the infiltrate, but only rarely in the direct vicinity of the HRS cells, whereas CTLA-4 shows a more diffuse presence [15]. Likewise, a small number of scattered IL-17- positive cells can be found in the reactive infiltrate. Th17 cells are generally pro-inflammatory, but given the abundance of TGF-β and IL-6 in the Hodgkin microenvironment, the observed IL-17- positive cells might be yet another type of regulatory cells, termed Treg17 cells. Although the vast majority of studies indicate that the CD4+ T cells in cHL are (anergic) Th2 cells and Treg cells, some studies showed a predominant Th1-type pattern in whole lymph node cell suspensions, with a mild increase in EBV-positive cHL [16]. These findings 4 Microenvironment, Cross-Talk, and Immune Escape Mechanisms are not contradictory, as these Th1-like cells are located mainly outside the areas where R-S cells and T cell rosettes are found [17, 18]. 73 The CD4+ T cells in NLPHL resemble the CD4+ T cells in cHL, regarding the expression of CD45RO, CD69, CTLA4, and CD28 and lack of CD26. However, the T cells in NLPHL do not express CD40L, and a significant proportion of the T cells that immediately surround the LP cells express CD57 and PD-1 [19, 20]. Similar to the Th2 cells in cHL, the rosetting cells in NLPHL strongly express the Th2-associated transcription factor c-Maf (Fig. 4.3; [4]). Characterization of the cytokine profile of the CD4+CD57+ T cell subset shows lack of IL-2 and IL-4 mRNA, but elevated interferon-γ (IFN- γ) mRNA levels in comparison to CD57+ T cells from tonsils. Stimulation of these cells fails to induce IL-2 and IL-4 mRNA levels [21], which is similar to the lack of cytokine induction upon stimulation of the CD26− T cells in cHL. In normal tissue, CD4+CD57+ T cells are found almost exclusively in the light zone of reactive germinal centers and also lack CD40L expression. CD57 is known as an activation marker, but it has also been demonstrated to be a marker for senescent cells. Senescence is the phenomenon by which normal diploid cells lose the ability to divide, normally after about 50 cell divisions. PD-1+ T follicular helper cells are present in NLPHL; Fig. 4.3 T cells in nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). Immunohistochemistry of an NLPHL case showing a variable but usually high number of reactive T cells that express CD57. In this case these T cells form a rosette around the tumor cells (upper panel left). The CD57+ T cells also express the transcription factor c-Maf, indicating a Th2-type nature (upper panel right). In addition, these cells express the T follicular helper cell-associated markers PD-1 (lower panel left) and BCL-6 (lower panel right) 4.1.5 T Cell Subsets in NLPHL L. Visser et al. 74 these cells normally provide help to B cells during the germinal center reaction. Another cell population, consisting of CD4+CD8+ dual positive T cells, has been reported to be present in more than 50% of NLPHL tumors. A similar population was found in reactive lymph nodes with progressively transformed germinal centers, which can also be seen in conjunction with NLPHL. In normal peripheral blood, they constitute 1–2% of T cells. The function of these cells is ill defined, and currently they are considered to be potent immunosuppressors and/or to have high cytotoxic potential [22]. 4.1.6 Fibrosis and Sclerosis The presence of bands of collagen surrounding nodules and blood vessels is typical of the nodular sclerosis subtype. Several factors can induce the activation of fibroblasts and the subsequent deposition of extracellular matrix proteins. The Th2 cells in cHL might provide a profibrogenic microenvironment by the production of the Th2 cytokine IL-13. IL-13 is expressed at a higher level in nodular sclerosis than in mixed cellularity cHL. Moreover, the percentage of IL-13 receptor-positive fibroblasts is increased in nodular sclerosis cHL cases [23]. IL-13 stimulates collagen synthesis in vitro and also stimulates the production of TGF-β, another potent stimulator of fibrosis. TGF-β can interact with basic fibroblast growth factor (bFGF) to induce formation of fibrosis in cHL. In a mouse model for fibrosis, the simultaneous application of TGF-β and bFGF causes persistent fibrosis [24]. Both TGF-β and bFGF are produced by HRS cells as well as the reactive background [25, 26]. They are produced more prominently in nodular sclerosis than in mixed cellularity cHL [27]. The third factor that stimulates fibroblasts in cHL is the engagement of CD40. CD40, a member of the tumor necrosis factor receptor (TNFR) superfamily, can be upregulated on fibroblasts by IFN-γ. The ligand of CD40 (CD40L) is present on activated T cells, mast cells, and eosinophils present in the cHL microenvironment. 4.1.7 osinophils, Plasma Cells, E Mast Cells, and B Cells Presence of eosinophils in the reactive infiltrate can be promoted by both IL-5, produced by Th2 cells, and by IL-9. In cHL patients with eosinophilia in the peripheral blood, HRS cells produce IL-5 and IL-9 [28]. In addition, eosinophils are attracted to cHL tissues by the production of the chemokine CCL11, especially in nodular sclerosis cHL. CCL11 levels can be enhanced by the production of tumor necrosis factor-α (TNF-α) by the HRS cells, which in turn can induce CCL11 production in fibroblasts. This process is specific for cHL since other lymphomas with tissue eosinophilia show no expression of CCL11 [29]. HRS cells also produce CCL28 (MEC), and expression of CCL28 correlates with the presence of eosinophils and plasma cells in cHL. CCL28 attracts eosinophils by signaling through the chemokine receptor CCR3 and attracts plasma cells through CCR10 [30]. CCL5 is produced at high levels by the reactive infiltrate in cHL and can attract eosinophils as well as mast cells. CCL5 and IL-9 may both contribute to the attraction of mast cells in cHL [31]. The stimulation and recruitment of eosinophils in cHL can be illustrated in bone marrow biopsies that often show enhanced granulopoiesis with many eosinophils in the absence of HRS cells. IL-6 produced by HRS cells in some cases of cHL may explain the presence of variable numbers of plasma cells [32]. B cells that express CD20, CD21, IgM, and bcl-6 can be found in the microenvironment of cHL [33]. It is possible that these cells are remnants of the original lymph node B cell areas. Plasma cells, mast cells, and eosinophils are generally absent in NLPHL. 4.2 ross-Talk between HRS C Cells and Microenvironment (Fig. 4.4) 4.2.1 Factors Supporting Tumor Growth It is likely that HL tumor cells originate from a precursor B cell that has become addicted to 4 Microenvironment, Cross-Talk, and Immune Escape Mechanisms 75 Fig. 4.4 Schematic overview of the cross-talk between Hodgkin/Reed-Sternberg (HRS) cells and the microenvironment. HRS cells attract specific subsets of cells by producing chemokines, are dependent on growth factors, and use mechanisms of immunosuppression and immune escape. Arrows indicate stimulating effects; the other lines indicate inhibitory effects activating and growth-supporting stimuli during a deregulated immune response. Many additional events are needed to account for the highly deregulated malignant phenotype of HRS and LP cells. Although the tumor cells attain multiple alternative mechanisms to circumvent the dependence on growth-stimulating signals from the reactive infiltrate, they usually are not selfsufficient at the time of diagnosis. This is reflected by the inability to generate cell lines from primary HL cell suspensions. IL-3 can function as a growth factor for B cells and is produced by activated Th2 cells, mast cells, and eosinophils. Its functions include protection against apoptosis and stimulation of proliferation. Most HRS cells express the IL-3 receptor, and exogenous IL-3 promotes growth of cHL cell lines. Costimulation of HL cell lines with IL-3 and IL-9 results in a further enhancement of cell growth [34]. There is no evidence that HRS cells produce IL-3, so this signaling pathway depends on IL-3 produced by the reactive infiltrate. In contrast, IL-7 is most likely an autocrine as well as a paracrine growth factor for HRS cells, since HRS cells express both the IL-7 receptor and produce IL-7 [35]. cHL cell lines also produce IL-7, albeit at very low levels, and anti-IL-7 treatment has some effect on cell growth. Addition of IL-7 to HL cell line cultures increased proliferation and protected against apoptosis. Moreover, fibroblasts isolated from cHL tissues are able to produce IL-7 [36]. Other growth factors important for HRS cells are IL-9, IL-13, IL-15, and, possibly, IL-6. IL-9 is expressed by the tumor cells and not by the infiltrating cells, and the IL-9 receptor is expressed on cHL tumor cells and mast cells. IL-9 supports tumor growth in cell lines and functions as an autocrine factor in cHL tissue [31]. IL-13 produced by HRS cells as well as the L. Visser et al. 76 surrounding T cells drives proliferation and is mostly autocrine [37]. Both IL-15 and the IL-15R are expressed by HRS cells. IL-15 induces proliferation of HL cell lines and protects them against apoptosis [38]. IL-6 is mainly produced by HRS cells and occasionally by the infiltrating cells [32]. In general, IL-6 is found at higher levels in EBV-positive cases [39]. IL-6 might have an autocrine effect although neutralizing antibodies have no effect on the growth of cHL cell lines. The signaling of cytokines upon binding to their receptors leads to activation of the JAK- STAT pathway. This pathway is constitutively activated in HL cell lines [40, 41], and several of the STAT family members are expressed in HRS cells of primary cHL cases [42, 43]. In addition to the presence of cytokines, amplifications of 9p24.1, including the JAK2 gene locus found in part of the cHL cases [44], can further enhance constitutive activation of this pathway. Functional studies in cHL cell lines have shown that STAT3 is involved in proliferation [45], while STAT1 and STAT6 play a role in protection against apoptosis [46]. Binding of IL-21 to the IL-21R expressed on HL cell lines causes phosphorylation of STAT5 and induces proliferation [47]. HRS cells express several members of the TNFR superfamily including CD30, which has been used as a marker for cHL since the early 1980s. The CD30 ligand (CD30L) is expressed on eosinophils [48] and mast cells [49] that are present in the cHL infiltrate. Circulating eosinophils in cHL patients also have increased expression levels of CD30L [48]. Binding of CD30L to CD30 causes enhanced secretion of IL-6, TNFα, lymphotoxin-α, increased expression of ICAM-1 and B7, and, possibly, increased clonogenic growth and protection against apoptosis in cHL cell lines [50]. Another TNFR expressed on HRS cells is CD40. CD40 is generally found on B cells, and B cells can be activated through CD40. In vitro rosetting of activated CD4+ T cells around HRS cells is mediated through the CD40L adhesion pathway [51]. Engagement of CD40 is important for the prevention of apoptosis. Similar to stimulation of CD30, stimulation of HRS cell lines with CD40L causes enhanced secretion of several cytokines and upregulation of costimulatory molecules [50]. Several receptor tyrosine kinases (RTKs) are expressed by HRS cells and can have a role in cell growth. Their ligands are expressed on cells present in the microenvironment or by the HRS cells themselves. Inhibition of PDGFRA, expressed by the HL tumor cells, by imatinib blocks proliferation. Its ligand, PDGFA, is also produced by the HRS cells indicating autocrine signaling [52]. DDR1 [53] and DDR2 [52] can protect HRS cells from cell death by binding to collagen, which is present in the immediate surrounding of HRS cells. Knockdown of DDR1 decreases survival of the L428 cHL cell line [53]. TRKA, the receptor for NGF, is expressed by granulocytes [52], and TRK inhibition decreases growth of cHL cell lines [54]. EPHB1 and its ligand ephrin-B1 are both expressed by HRS cells [52]. The HGF receptor c-Met is expressed on HRS cells and inhibition causes G2/M cell cycle arrest in HL cell lines. HGF is produced by the tumor cells in a small group of patients and by dendritic reticulum cells [55]. Insulin-like growth factor receptor (IGF-1R) is expressed in 55% of cHL patients, and inhibition of IGF-1R decreases cell growth and induces G2/M cell cycle arrest in HL cell lines [56]. Its ligand IGF-1 is expressed by cells in the microenvironment [57]. PDGFRA, DDR2, EPHB1, RON, TRKA, and TRKB are found especially in EBV-negative HL [58], while DDR1 is upregulated by LMP1 [53]. The Notch1 receptor is an upstream regulator of NFκB [59]. It is highly expressed by HRS cells and stimulation via Jagged1 induces proliferation and survival of cHL cell lines [60]. 4.2.2 Shaping the Environment In addition to the production of several growth factors, HRS cells also produce large amounts of chemokines to attract specific beneficial or nonreacting cells. The lack of CD26 on the T cells surrounding the HRS cells may result in an incapability to cleave chemokines and thereby modulates the chemotactic effects exerted by the HRS cells. The attraction of specific populations of cells is an important immune escape mechanism exerted by the tumor cells. 4 Microenvironment, Cross-Talk, and Immune Escape Mechanisms The most abundant and cHL-specific chemokine is CCL17 (TARC); it binds to CCR4 on Th2 cells, Treg cells, basophils, and monocytes. CCL17 is highly expressed by HRS cells in ~95% of cHL patients but not in NLPHL and most non- Hodgkin lymphomas [61, 62]. CCL17 can be measured in serum and plasma and is a sensitive and specific marker reflecting cHL tumor burden [63–67]. High expression levels of CCL17 might explain the influx of lymphocytes with a Th2and Treg-like phenotype, and CCL17-positive cases are indeed associated with a higher percentage of CCR4-positive cells (Fig. 4.2; [62, 68]). In turn, Th2-type cytokines (IL-4, IL-13) can induce the production of CCL17 by HRS cells. CCR4-positive T cells are found especially in the rosettes immediately surrounding the HRS cells [15, 69]. CCL22 is another chemokine that has a similar function as CCL17. High CCL22 protein expression levels were found in the cytoplasm of HRS cells in 90–100% of cHL patients and also in tumor cells in the majority of NLPHL and non-HL patients [70–73]. CCL22 production can also be stimulated by Th2 cytokines, IL-4 and IL-13, and may reinforce the attraction of Th2 and Treg cells, initiated by CCL17. Stimulation of the IL-21 receptor on HRS by IL-21 activates STAT3, which can induce CCL20 (MIP3α) production. CCL20 in turn attracts memory T cells and Treg cells [74]. HRS cells express both IL-21 and the IL-21 receptor, indicating presence of an autocrine signaling loop. The expression of some chemokines is more pronounced in EBV-positive cHL (i.e., CXCL9 and CXCL10), and as a result the composition of the reactive background is somewhat different from that in EBV-negative cHL, with a slightly higher proportion of CD8+ T cells in EBV-positive cases and more T cells with a Tr-1 phenotype (expressing LAG3, ITGA2, and ITGB2) [75]. T cell recruitment is also enhanced by the upregulation of adhesion molecules on endothelial cells, induced by LTα [76] produced by HRS cells [77]. In addition to attracting specific cell subsets by chemotaxis, HRS cells also shape their environment by inducing differentiation of specific T cell subsets that are favorable for HRS cell survival and growth. The expression of IL-13 by the 77 HRS cells stimulates differentiation of naïve T cells to Th2 cells [37]. The production of IL-7 by HRS cells and fibroblasts can induce proliferation of Tregs [36]. Also, cHL cell lines with antigen- presenting functions like KMH2 and L428 have been shown to promote the differentiation of Treg like cells in vitro (expressing CD4, CD25, FoxP3, CTLA4, and GITR and producing large amounts of IL-10). Interestingly, these cell lines can also induce the formation of CD4+ cytotoxic T cells (expressing granzyme B and TIA-1) that can kill tumor cells directly, suggesting that CD4+ cytotoxic T cells have the potential to attack tumor cells in vivo [78]. 4.3 Immune Escape Mechanisms (Fig. 4.4) 4.3.1 Antigen Presentation The importance of antigen presentation in the pathogenesis of cHL has been suggested by the association of specific HLA subtypes with increased cHL incidence. cHL is more common in Caucasians as compared to Asians and about 4.5% of cHL cases occur in families [79, 80]. A three- to sevenfold increased risk has been observed in first-degree relatives and siblings. In monozygotic twins, the co-twin has an approximate 100-fold increased risk of developing cHL compared to dizygotic twins [81]. From the 1970s, a number of serological HLA types have been associated with the occurrence of cHL. More recently, a genetic screen of the entire HLA region showed a strong association between the HLA-A gene and EBV-positive cHL and the HLA class II region with EBV-negative cHL [82, 83]. Four independent genome-wide association studies have confirmed that the HLA region is the strongest genetic susceptibility locus in cHL [84– 87]. In EBV-positive cHL, it can be hypothesized that this association is related to insufficient presentation of EBV antigenic peptides. These antigenic peptides most likely are derived from the latency type II genes that are expressed in cHL, i.e., LMP1, LMP2, and EBV-related nuclear antigen 1 (EBNA1). EBV partially escapes cytotoxic L. Visser et al. 78 immune responses by downregulating immunodominant latent genes (EBNA2 and EBNA3). In addition, the glycine-alanine repeat in EBNA1 largely prevents its presentation by HLA class I by blocking its degradation into antigenic peptides through the proteasome [88]. However, subdominant immune responses to LMP2 and to a lesser extent LMP1 are present in healthy EBV- infected individuals [89]. In fact, adoptive immunotherapy in relapsed EBV-positive cHL has been used in some small studies with success. In these studies, peripheral blood from cHL patients was used to generate EBV-specific cytotoxic T cells in vitro, and these were reinfused. Some durable complete responses were observed, with better responses if the cytotoxic T cells were specifically targeted to LMP2 [90–92] (Fig. 4.4). Interestingly, the genetic association of the HLA- A gene with EBV-positive cHL is attributed to the presence of the HLA-A∗01 type and absence of the HLA-A∗02 type [93]. HLA-A∗01 is known to have a low affinity for LMP2- and LMP1- derived antigenic peptides, while HLA-A∗02 can present these peptides very well. This suggests that EBV-positive cHL is more likely to occur after primary EBV infection if an individual’s set of HLA class I molecules cannot properly present LMP2 and LMP1 to the immune system [94]. 4.3.2 HLA Class I Expression Defects in the antigen-presenting pathways are very common in solid malignancies, as well as in many B cell lymphomas, and are an obvious mechanism to escape from antitumor immune responses. In EBV-negative cHL, less than 20% of cases retain expression of cell surface HLA class I on the HRS cells at the time of diagnosis. Paradoxically, HLA class I expression by HRS cells is retained in ~75% of EBV-positive cHL patients [95–97]. One common mechanism of HLA class I loss is presence of somatic mutations in the β2-microglobulin gene. This leads to loss of β2-microglobulin protein, which is necessary for HLA class I assembly and transport to the cell surface. Other mechanisms also appear to be involved as immunohistochemistry has shown cytoplasmic β2-microglobulin expression in part of the cases that lost HLA class I heavy chain expression [98]. These different mechanisms may indicate that downregulation of HLA class I is based on clonal selection by continuous cytotoxic immune responses. This may be related to the presence of antigenic peptides that are related to malignant transformation or disease progression. However, downregulation of HLA class I generally induces activation of natural killer (NK) cells. These cells contain HLA class I-specific inhibitory receptors and are sparse in the reactive infiltrate of cHL. The inhibitory receptors can also be engaged by the nonclassical HLA class I-like molecule known as HLA-G. In about two thirds of the HLA class I-negative cHL cases, the HRS cells indeed express HLA-G [98]. Besides NK cell inhibition, HLA-G might also induce Treg cells and inhibit cytotoxic T cell responses. Another immune escape mechanism consists of the proteolytic cleavage of MHC (HLA) class I-related chain-A (MIC-A) by ERp5 and ADAM10, which are both expressed by HRS cells. MIC-A is a membranous ligand for the activating NKG2D receptor present on cytotoxic T cells. In addition, the NKG2D receptor expression by these cytotoxic T cells is reduced in the presence of TGF-β [99]. 4.3.3 HLA Class II Expression HLA class II cell surface expression on HRS cells is lost in approximately 40% of all cHL patients [95]. In addition, translocations involving CIITA have been found in 15% of cHL patients and may result in partial downregulation of HLA class II expression [101]. The absence of HLA class II is weakly related to extranodal disease, EBV-negative status, and absence of HLA class I cell surface expression. Lack of HLA class II expression has been associated with adverse failure-free survival and relative survival and is independent of other prognostic factors [95]. It can be hypothesized that antigen presentation in the context of HLA class II is involved in recruitment and activation of CD4+ T cells early in cHL pathogenesis. Under the influence of immunomodulating mechanisms, these T cells are important in providing trophic factors for HRS cells 4 Microenvironment, Cross-Talk, and Immune Escape Mechanisms and also have a role in inhibiting Th1 responses. In the initial stages of cHL pathogenesis, HRS cells are probably highly dependent on the reactive infiltrate and expression of HLA class II, but as the lymphoma develops, this dependency may weaken because of alternative trophic and immunosuppressive strategies. Thus, downregulation of HLA class II without loss of viability of HRS cells might occur when the HRS cells have grown less dependent on the reactive infiltrate. This is supported by the finding that downregulation of HLA class II is associated with extranodal disease [95]. 4.3.4 Immune Checkpoints Immune checkpoint molecules have gained much attention due to their use as treatment targets. Both CTLA-4 and PD-1 blockade have shown remarkable results in cHL patients in clinical trials. CTLA-4 is expressed exclusively on T cells upon activation. It gives an inhibitory signal early after T cell activation, by binding to CD80/CD86 with a higher avidity than the costimulatory molecule CD28. This limits T cell activation and proliferation [101, 102]. Interestingly, CTLA-4 is present on the characteristic CD26− T cells in HL [15]. Moreover, HL cell lines are able to induce differentiation of naïve T cells into CTLA4+ Tregs [78]. So far, two clinical trials have exploited the use of a monoclonal antibody targeting CTLA-4 in relapsed and refractory HL after allogeneic hematopoietic cell transplantation. Objective response rates were observed in 2 out of 14 and 1 out of 7 cases [103, 104]. The interaction partner of PD-L1, PD-1, is present on activated T cells, B cells, macrophages (which also express PD-L1), and NK cells within the microenvironment [105, 106]. PD-L1 is highly expressed on HRS cells [105, 107], due to a selective amplification of the PD-L1 region on 9p24.1 [44], activation of AP-1 and LMP-1 [107], or chromosomal alterations involving the CIITA locus [100]. Anti-PD-1 therapy in relapsed and refractory HL patients, using the monoclonal antibodies nivolumab or pembrolizumab, showed objective response rates in 65–87% of the cHL 79 patients [108–111]. The mechanism of action of PD-1 blockade in HL remains unknown, but multiple mechanisms have been studied. In contrast to solid tumors where CD8+ cytotoxic T cells seem to be the main effector cells [112], CD4+ T cells might have an important role in mediating the antitumor immune response in HL. CD8+ T cells recognize the tumor cells through (neo)antigens presented in the context of HLA class I, which can ultimately lead to eradication of the tumor cells. However, HLA class I is often absent on HRS cells, making a central role for CD8+ T cells in immune checkpoint efficacy unlikely [96]. In HL, the inflammatory infiltrate is mainly dominated by CD4+ T cells, which are more often in direct contact with the HRS cells when compared to CD8+ T cells. In addition, CD4+PD-1+ T cells are more frequently bound to PD-L1+ HRS cells [113]. The majority of complete responders to nivolumab lack membranous HLA class I expression, while being positive for membranous HLA class II expression. Also, presence of HLA class II is predictive for a prolonged progression-free survival in patients treated with nivolumab >12 months after myeloablative autologous stem cell transplantation, in contrast to presence of HLA class I [114]. Although many studies on PD-1 blockade focused on T cells, expression of PD-1 on T cells in direct contact with HRS cells is rare, and their numbers are significantly lower in cases with PD-L1 gain [115]. Interestingly, exhausted PD-1+ CD3+CD56hiCD16− NK cells are enriched in HL, and their activation can be inhibited by PD-L1+CD163+CD14+ tumor- associated macrophages, which are also increased in HL. This inhibition was effectively reversed by PD-1 blockade [106]. This indicates the importance of other cell types in responses to PD-1 blockade that are currently less well characterized. An interesting molecule with regard to the role of CD4+ T cells in responses to anti-PD-1 therapy is LAG-3. LAG-3 is an immune checkpoint molecule expressed on activated T cells, NK cells, B cells, and plasmacytoid dendritic cells [116]. The main interaction partner for LAG-3 is HLA class II, to which LAG-3 binds with higher affinity than CD4 [117]. LAG-3 is upregulated on Tregs, and LAG-3-positive lymphocytes are enriched in the 80 proximity of HRS cells [118, 119]. Increased LAG-3 expression was observed especially in EBV-positive cHL cases [118, 120]. Interestingly, the percentage of LAG-3-positive cells was enriched in CD4+ T cells that express a high intracellular CTLA-4 and GITR, but not FOXP3+ [118]. The GITRhi CD4+ T cells are frequently in direct contact with HRS cells [15]. Moreover, CD4+LAG-3+ cells are significantly expanded in patients with active disease, which is in concordance with the ability of HL cell line supernatant to increase expansion of CD4+LAG-3+ regulatory T cells within PBMCs. In addition, higher FOXP3 and LAG-3 expression on tumor-infiltrating lymphocytes is associated with decreased LMP1- and LMP2-specific CD8+ T cell function [118]. Altogether this implicates an important role for LAG-3 in inhibiting (EBV) mediated cellular immunity in HL and points to LAG-3 as an interesting treatment target in combination with PD-1 blockade. Currently, more and more immune checkpoint molecules are emerging as potential targets for therapy. Some of these are less well studied in the context of HL. For example, HRS cells express HVEM and CD200/CD200R [121] in addition to the earlier mentioned checkpoints, whereas TIM- 3+ T cells are present within the inflammatory infiltrate [120], indicating the complexity of immunosuppressive mechanisms within the HL microenvironment. L. Visser et al. nosuppressive cytokines TGF-β and IL-10. TGF-β is produced by HRS cells in nodular sclerosis cHL [25, 26], whereas IL-10 is more frequently found in EBV-positive (mixed cellularity) cHL [122, 123]. In normal cells, TGF-β is produced in an inactive form, which can be activated by acidification. TGF-β produced by cHL cell lines is active at a physiological pH and has a high molecular weight [124]. The same high molecular weight form of TGF-β can also be found in the urine of cHL patients [125] indicating that in patients HRS cells are able to produce the active TGF-β form. Tregs present in the microenvironment of cHL are highly immunosuppressive and contain Tr1 (IL-10-producing Tregs) as well as CD4+CD25+ Tregs. IL-10, cell-cell contact, and CTLA4 play a main role in executing their immunosuppressive function [126]. In addition, HRS cells express galectin-1, an animal lectin, which can cause apoptosis in activated T cells, induce differentiation into Treg cells, and contribute to the elimination of an effective antitumor response in cHL [127]. Galectin-1 expression blocks CD8+ T cell responses against LMP1 and LMP2 in EBV- positive cHL [128]. HRS cells express FAS and the FAS ligand. However, there are some mechanisms protecting the HRS cells from apoptosis induction, such as FAS mutations in a small proportion of cases and c-FLIP overexpression in all cases [129]. Presumably, activated Th1 and CD8+ T cells expressing FAS are driven into apoptosis by the FAS ligand expression on the 4.3.5 Immunosuppression HRS cells. Also, indoleamine 2,3-dioxygenase (IDO), a known immunosuppressor, is expressed As normal B cells are professional antigen- by histiocytes, dendritic cells, and endothelial presenting cells, HRS cells are expected to pres- cells in the microenvironment of cHL. IDO is ent antigens to the immune system, at least early found more often in EBV-positive HL, upreguin disease pathogenesis. Indeed, most compo- lates the number of Tregs [130], and potentially nents of the HLA class I and HLA class II blocks the CD8+ T cell response [131]. In EBV- antigen-presenting pathways have been detected positive cHL, the Th1-inducing cytokine IL-12 is in the HRS cells at the time of diagnosis. expressed in T cells surrounding the HRS cells, However, Th1 cells are not actively attracted by and its presence suggests that these T cells have the HRS cells and CD8+ T cells are relatively the potential to induce antitumor activity [132]. scarce. Moreover, HRS cells have gained the However, an EBV-induced IL-12-related cytocapacity to prevent CD8+ T cells from attacking kine called EBI3 can block this Th1 response and by producing high amounts of the strongly immu- is produced by HRS cells [133]. 4 Microenvironment, Cross-Talk, and Immune Escape Mechanisms 4.4 Prognostic Impact of the Microenvironment Several research groups studied the cHL reactive infiltrate in relation to prognosis. Gene expression profiling of whole tissue and subsequent validation by immunohistochemistry showed that high numbers of CD68-positive cells are related to adverse outcome [134]. In a meta-analysis of almost 3000 patients, a high density of CD68+ tumor-associated macrophages predicted overall survival, shorter progression-free survival, and poor disease survival in adult cHL [135]. Similar findings were obtained for CD163+ macrophages in this study. Analysis of 100 pediatric cHL revealed that especially M2 macrophages, characterized by co-expression of CD163 and c-Maf, are associated with poor survival, while M1 macrophages are associated with better survival [136]. In some studies tumor-associated macrophages were associated with EBV-positive tumors [135, 137] and presence of other cell types in the microenvironment, such as cytotoxic T cells [136] and mast cells [138]. Patients with a higher degree of mast cell infiltration or with tissue eosinophilia have an adverse failure-free survival, probably because the CD30L expression by these cell types is advantageous to the HRS cells [48, 49, 138]. Large numbers of Th2 cells in the microenvironment, as determined by c-Maf expression, correlate with improved disease-free survival [14]. Also, increased numbers of infiltrating Treg cells seem to correlate with improved survival as this effect was observed in two out of three studies [14, 139, 140]. Accordingly, a high percentage of activated CD8+ granzyme B+ T cells is a strong indicator of unfavorable clinical outcome [141]. More recently, a high proportion of Treg cells and the associated anergic phenotype of the microenvironment has been associated with a shorter time to progression [137]. A high CD4/CD8 T cell ratio was associated with treatment failure [142]. A high ratio of FoxP3 to cytotoxicity markers granzyme B [140] or Tia-1 [139] gives the best predictive value for a good prognosis and has also been correlated to the presence of macrophages 81 [136, 138], which might—in part—explain these effects. In other malignancies the presence of Tregs and the absence of CD8+ T cells have been associated with adverse prognosis. One explanation of this opposite effect might be that HRS cells are expected to behave more aggressively as they develop a stronger independency from the reactive infiltrate. In this situation a hostile microenvironment is allowed, because the HRS cells have acquired alternative immune evasive strategies. This theory fits with the adverse prognostic impact of absence of HLA class II expression. 4.5 Conclusion The microenvironment is a fundamental component of the tumor mass and an essential pathogenetic factor in cHL and NLPHL. It supplies the tumor cells with growth factors and inhibits antitumor immune responses. In fact, it could be stated that the infltrate does not consist of ‘innocent bystanders’ but contains ‘guilty opportunists’ [31]. As the tumor cells and the reactive infiltrate grow up together, there is an extensive cross-talk between these two components. The tumor cells actively attract and shape their environment for their own benefit and make use of a number of mechanisms to fend off antitumor immune responses. References 1. Poppema S, Delsol G, Pileri SA et al (2008) Nodular lymphocyte predominant Hodgkin lymphoma. In: Swerdlow SH, Campo E, Harris NL et al (eds) WHO classification of tumours of haematopoietic and lymphoid tissues. IARC, Lyon 2. Stein H, Delsol G, Pileri SA et al (2016) Classical Hodgkin lymphoma, introduction. In: Swerdlow SH, Campo E, Harris NL et al (eds) WHO classification of tumours of haematopoietic and lymphoid tissues. IARC, Lyon 3. Fan Z, Natkunam Y, Bair E, Tibshirani R, Warnke RA (2003) Characterization of variant patterns of nodular lymphocyte predominant Hodgkin lymphoma with immunohistologic and clinical correlation. Am J Surg Pathol 27:1346–1356 4. Atayar C, van den Berg A, Blokzijl T et al (2007) Hodgkin lymphoma associated T-cells exhibit a L. Visser et al. 82 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. transcription factor profile consistent with distinct lymphoid compartments. J Clin Pathol 60:1092–1097 Carbone A, Gloghini A, Cabras A et al (2009) Differentiating germinal center-derived lymphomas through their cellular microenvironment. Am J Hematol 84:435–438 Sattarzadeh A, Visser L, Rutgers B, Diepstra A, van den Berg A (2016) Characterization of the microenvironment of nodular lymphocyte-predominant Hodgkin lymphoma. Int J Mol Sci 17:e2127 Huppmann AR, Nicolae A, Slack GW et al (2014) EBV may be expressed in the LP cells of nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) in both children and adults. Am J Surg Pathol 38:316–324 Oudejans JJ, Jiwa NM, Kummer JA et al (1996) Analysis of major histocompatibility complex class I expression on Reed-Sternberg cells in relation to the cytotoxic T-cell response in Epstein-Barr virus- positive and -negative Hodgkin’s disease. Blood 87:3844–3851 Goedert JJ, Cote TR, Virgo P et al (1998) Spectrum of AIDS-associated malignant disorders. Lancet 351:1833–1839 Biggar RJ, Jaffe ES, Goedert JJ et al (2006) Hodgkin lymphoma and immunodeficiency in persons with HIV/AIDS. Blood 108:3786–3791 Poppema S (1996) Immunology of Hodgkin’s disease. Ballieres Clin Haematol 9:447–457 Wolf M, Albrecht S, Marki C (2008) Proteolytic processing of chemokines: implications in physiological and pathological conditions. Int J Biochem Cell Biol 40:1185–1198 Von Bonin A, Huhn J, Fleischer B (1998) Dipeptidyl- peptidase IV/CD26 on T cells: analysis of an alternative T-cell activation pathway. Immunol Rev 161:43–53 Schreck S, Friebel D, Buettner M et al (2009) Prognostic impact of tumour-infiltrating Th2 and regulatory cells in classical Hodgkin lymphoma. Hematol Oncol 27:31–39 Ma Y, Visser L, Blokzijl T et al (2008) The CD4+CD26− T-cell population in classical Hodgkin’s lymphoma displays a distinctive regulatory T-cell profile. Lab Investig 88:482–490 Greaves P, Clear A, Owen A et al (2013) Defining characteristics of classical Hodgkin lymphoma microenvironment T helper cells. Blood 122:2856–2863 Wu R, Sattarzadeh A, Rutgers B, Diepstra A, van den Berg A, Visser L (2016) The microenvironment of classical Hodgkin lymphoma: heterogeneity by Epstein-Barr virus presence and location within the tumor. Blood Cancer J 6:e417 Cader FZ, Schackmann RCJ, Hu X et al (2018) Mass cytometry of Hodgkin lymphoma reveals a CD4(+) regulatory T-cell-rich and exhausted T-effector microenvironment. Blood 132:825–836 19. Nam-Cha SH, Roncador G, Sanchez-Verde L et al (2008) PD-1, a follicular T-cell marker useful for recognizing nodular lymphocyte-predominant Hodgkin lymphoma. Am J Surg Pathol 32:1252–1257 20. Sattarzadeh A, Diepstra A, Rutgers B, van den Berg A, Visser L (2015) CD57+ T-cells are a subpopulation of T-follicular helper cells in nodular lymphocyte-predominant Hodgkin lymphoma. Exp Hematol Oncol 4:27 21. Atayar C, Poppema S, Visser L et al (2006) Cytokine gene expression profile distinguishes CD4+/CD57+ T-cells of nodular lymphocyte predominance type of Hodgkin lymphoma from their tonsillar counterparts. J Pathol 208:423–430 22. Rahemtullah A, Harris NL, Dorn ME et al (2008) Beyond the lymphocyte predominant cell: CD4+CD8+ T-cells in nodular lymphocyte predominant Hodgkin lymphoma. Leuk Lymphoma 49:1870–1878 23. Ohshima K, Akaiwa M, Umeshita R et al (2001) Interleukin-13 and interleukin-13 receptor in Hodgkin’s disease: possible autocrine mechanism and involvement in fibrosis. Histopathology 38:368–375 24. Shinozaki M, Kawara S, Hayashi N et al (1997) Induction of subcutaneous tissue fibrosis in newborn mice by transforming growth factor-b – simultaneous application with basic growth factor causes persistent fibrosis. Biochem Biophys Res Commun 237:292–296 25. Kadin M, Butmarc J, Elovic A et al (1993) Eosinophils are the major source of transforming growth factor-beta 1 in nodular sclerosing Hodgkin’s disease. Am J Pathol 142:11–16 26. Newcom SR, Gu L (1995) Transforming growth factor beta 1 messenger RNA in Reed-Sternberg cells in nodular sclerosing Hodgkin’s disease. J Clin Pathol 48:160–163 27. Ohshima K, Sugihara M, Suzumiya J et al (1999) Basic fibroblast growth factor and fibrosis in Hodgkin’s disease. Pathol Res Pract 195:149–155 28. Samoszuk M, Nansen L (1990) Detection of interleukin-5 messenger RNA in Reed-Sternberg cells of Hodgkin’s disease with eosinophilia. Blood 75:13–16 29. Jundt F, Anagnostopoulos I, Bommert K et al (1999) Hodgkin/Reed-Sternberg cells induce fibroblasts to secrete eotaxin, a potent chemoattractant for T cells and eosinophils. Blood 94:2065–2071 30. Hanamoto H, Nakayama T, Miyazato H (2004) Expression of CCL28 by Reed-Sternberg cells defines a major subtype of classical Hodgkin’s disease with frequent infiltration of eosinophils and/or plasma cells. Am J Pathol 164:997–1006 31. Glimelius I, Edstrom A, Amini RM et al (2006) IL-9 expression contributes to the cellular composition in Hodgkin lymphoma. Eur J Haematol 76:278–283 4 Microenvironment, Cross-Talk, and Immune Escape Mechanisms 32. Jucker M, Abts H, Li W et al (1991) Expression of interleukin-6 and interleukin-6 receptor in Hodgkin’s disease. Blood 77:2413–2418 33. Tudor CS, Distel LV, Eckhardt J et al (2013) B cells in classical Hodgkin lymphoma are important actors rather than bystanders in the local immune reaction. Hum Pathol 44:2475–2486 34. Aldinucci D, Poletto D, Nanni P et al (2002) Expression of functional interleukin-3 receptors on Hodgkin and Reed-Sternberg cells. Am J Pathol 160:585–596 35. Foss HD, Hummel M, Gottstein S et al (1995) Frequent expression of IL-7 gene transcripts in tumor cells of classical Hodgkin’s disease. Am J Pathol 146:33–39 36. Cattaruzza L, Gloghini A, Olivo K et al (2009) Functional coexpression of interleukin (IL)-7 and its receptor (IL-7R) on Hodgkin and Reed-Sternberg cells: involvement of IL-7 in tumor cell growth and microenvironmental interactions of Hodgkin’s lymphoma. Int J Cancer 125:1092–1101 37. Kapp U, Yeh WC, Patterson B et al (1999) Interleukin 13 is secreted by and stimulates the growth of Hodgkin and Reed-Sternberg cells. J Exp Med 189:1939–1946 38. Ullrich K, Blumenthal-Barby F, Lamprecht B et al (2015) The IL-15 cytokine system provides growth and survival signals in Hodgkin lymphoma and enhances the inflammatory phenotype of HRS cells. Leukemia 29:1213–1218 39. Herbst H, Samol J, Foss HD et al (1997) Modulation of interleukin-6 expression in Hodgkin and Reed- Sternberg cells by Epstein–Barr virus. J Pathol 182:299–306 40. Cochet O, Frelin C, Peyron J-F, Imbert V (2006) Constitutive activation of STAT proteins in the HDLM-2 and L540 Hodgkin lymphoma-derived cell lines supports cell survival. Cell Signal 18:449–455 41. Kube D, Holtick U, Vockerodt M et al (2001) STAT3 is constitutively activated in Hodgkin cell lines. Blood 98:762–770 42. Hinz M, Lemke P, Anagnostopoulos I, Hacker C et al (2002) Nuclear factor kappaB-dependent gene expression profiling of Hodgkin's disease tumor cells, pathogenetic significance, and link to constitutive signal transducer and activator of transcription 5a activity. J Exp Med 196:605–617 43. Skinnider BF, Elia AJ, Gascoyne RD et al (2002) Signal transducer and activator of transcription 6 is frequently activated in Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma. Blood 99:618–626 44. Green MR, Rodig S, Juszczynski P et al (2012) Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders; implications for targeted therapy. Clin Cancer Res 18:1611–1618 45. Baus D, Pfitzner E (2006) Specific function of STAT3, SOCS1, and SOCS3 in the regulation of proliferation and survival of classical Hodgkin lymphoma cells. Int J Cancer 118:1404–1413 83 46. Baus D, Nonnenmacher F, Jankowski S et al (2009) STAT6 and STAT1 are essential antagonistic regulators of cell survival in classical Hodgkin lymphoma cell line. Leukemia 23:1885–1893 47. Scheeren FA, Diehl SA, Smit LA et al (2008) IL-21 is expressed in Hodgkin lymphoma and activates STAT5: evidence that activated STAT5 is required for Hodgkin lymphomagenesis. Blood 111:4709–4715 48. Pinto A, Aldinucci D, Gloghini A et al (1996) Human eosinophils express functional CD30 ligand and stimulate proliferation of a Hodgkin’s disease cell line. Blood 88:3299–3305 49. Molin D, Edstrom A, Glimelius I et al (2002) Mast cell infiltration correlates with poor prognosis in Hodgkin’s lymphoma. Br J Haematol 119:122–124 50. Grüss HJ, Ulrich D, Braddy S et al (1995) Recombinant CD30 ligand and CD40 ligand share common biological activities on Hodgkin and Reed- Sternberg cells. Eur J Immunol 25:2083–2089 51. Carbone A, Gloghini A, Gattei V et al (1995) Expression of functional CD40 antigen on Reed- Sternberg cells and Hodgkin’s disease cell lines. Blood 85:780–789 52. Renné C, Willenbrock K, Küppers R et al (2005) Autocrine- and paracrine-activated receptor tyrosine kinases in classic Hodgkin lymphoma. Blood 105:4051–4059 53. Cader FZ, Vockerodt M, Bose S et al (2013) The EBV oncogene LMP1 protects lymphoma cells from cell death through the collagen-mediated activation of DDR1. Blood 122:4237–4245 54. Renné C, Minner S, Küppers R et al (2008) Autocrine NGFβ/TRKA signaling is an important survival factor for Hodgkin lymphoma derived cell lines. Leukemia Res 32:163–167 55. Xu C, Plattel W, van den Berg A et al (2012) Expression of the c-met oncogene by tumor cells predicts a favorable outcome in classical Hodgkin’s lymphoma. Heamatologica 97:572–578 56. Liang Z, Diepstra A, Xu C et al (2014) Insulin-like growth factor 1 receptor is a prognostic factor in classical Hodgkin lymphoma. PLOSone 9:e87474 57. Eppler E, Janas E, Link K et al (2015) Insulin-like growth factor I is expressed in classical and nodular lymphocyte-predominant Hodgkin’s lymphoma tumour and microenvironmental cells. Cell Tissue Res 359:841–851 58. Renné C, Hinsch N, Willenbrock K et al (2007) The aberrant coexpression of several receptor tyrosine kinases is largely restricted to EBV-negative cases of classical Hodgkin’s lymphoma. Int J Cancer 120:2504–2509 59. Schwarzer R, Dörken B, Jundt F (2012) Notch is an essential upstream regulator of NF-κB and is relevant for the survival of Hodgkin and Reed-Sternberg cells. Leukemia 26:806–813 60. Jundt F, Anagnostopoulos I, Förster R et al (2002) Activated Notch1 signaling promotes tumor cell proliferation and survival in Hodgkin and anaplastic large cell lymphoma. Blood 99:3398–3403 L. Visser et al. 84 61. Peh SC, Kim LH, Poppema S (2001) TARC, a CC chemokine, is frequently expressed in classic Hodgkin lymphoma but not in NLP Hodgkin lymphoma, T-cell-rich B-cell lymphoma, and most cases of anaplastic large cell lymphoma. Am J Surg Pathol 25:925–929 62. Van den Berg A, Visser L, Poppema S (1999) High expression of the CC chemokine TARC in Reed- Sternberg cells. A possible explanation for the characteristic T-cell infiltrate in Hodgkin’s lymphoma. Am J Pathol 154:1685–1691 63. Niens M, Visser L, Nolte IM et al (2008) Serum chemokine levels in Hodgkin lymphoma patients: highly increased levels of CCL17 and CCL22. Br J Haematol 140:527–536 64. Weihrauch MR, Manzke O, Beyer M et al (2005) Elevated levels of CC thymus and activation-related chemokine (TARC) in primary Hodgkin’s disease: potential for a prognostic factor. Cancer Res 65:5516–5519 65. Plattel WJ, van den Berg A, Visser L et al (2012) Plasma thymus and activation-regulated chemokine as an early response marker in classical Hodgkin’s lymphoma. Haematologica 97:410–415 66. Sauer M, Plütschow A, Jachimowicz RD et al (2013) Baseline serum TARC levels predict therapy outcome in patients with Hodgkin lymphoma. Am J Hematol 88:113–115 67. Plattel WJ, Alsada ZN, van Imhoff GW, Diepstra A, van den Berg A, Visser L (2016) Biomarkers for evaluation of treatment response in classical Hodgkin lymphoma: comparison of sGalectin-1, sCD163 and sCD30 with TARC. Br J Haematol 175(5):868–875 68. Ohshima K, Tutiya T, Yamaguchi T et al (2002) Infiltration of Th1 and Th2 lymphocytes around Hodgkin and Reed-Sternberg (H&RS) cells in Hodgkin disease: relation with expression of CXC and CC chemokines on H&RS cells. Int J Cancer 98:567–572 69. Ishida T, Ishii T, Inagaki A et al (2006) Specific recruitment of CC chemokine receptor 4-positive regulatory T cells in Hodgkin lymphoma fosters immune privilege. Cancer Res 66:5716–5722 70. Andrew DP, Chang MS, McNinch J et al (1998) STPC-1 (MDC) CC chemokine acts specifically on chronically activated Th2 lymphocytes and is produced by monocytes on stimulation with Th2 cytokines IL-4 and IL-13. J Immunol 16:5027–5038 71. Hedvat CV, Jaffe ES, Qin J et al (2001) Macrophage- derived chemokine expression in classical Hodgkin’s lymphoma: application of tissue microarrays. Mod Pathol 14:1270–1276 72. Imai T, Chantry D, Raport CJ et al (1998) Macrophage-derived chemokine is a functional ligand for the CC chemokine receptor 4. J Biol Chem 273:1764–1768 73. Maggio E, van den Berg A, Visser L et al (2002) Common and differential chemokine expression patterns in RS cells of NLP, EBV positive 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. and negative classical Hodgkin lymphomas. Int J Cancer 99:665–672 Lamprecht B, Kreher S, Anagnostopoulos I et al (2008) Aberrant expression of the Th2 cytokine IL-21 in Hodgkin lymphoma cells regulates STAT3 signaling and attracts Treg cells via regulation of MIP-3alpha. Blood 112:3339–3347 Morales O, Mrizak D, François V et al (2014) Epstein-Barr virus infection induces an increase of T regulatory type 1 cells in Hodgkin lymphoma patients. Br J Haematol 166:875–890 Fhu CW, Graham AM, Yap CT et al (2014) Reed- Sternberg cell-derived lymphotoxin-alpha activates endothelial cells to enhance T-cell recruitment in classical Hodgkin lymphoma. Blood 124:2973–2982 Foss H-D, Herbst H, Oelmann E et al (1993) Lymphotoxin, tumour necrosis factor and interleukin-6 gene transcripts are present in Hodgkin and Reed-Sternberg cells of most Hodgkin’s disease cases. Br J Haematol 84:627–635 Tanijiri T, Shimizu T, Uehira K et al (2007) Hodgkin’s Reed-Sternberg cell line (KM-H2) promotes a bidirectional differentiation of CD4+CD25+Foxp3+ T cells and CD4+ cytotoxic T lymphocytes from CD4+ naive T cells. J Leukoc Biol 82:576–584 Ferraris AM, Racchi O, Rapezzi D et al (1997) Familial Hodgkin’s disease: a disease of young adulthood? Ann Hematol 74:131–134 Glaser SL, Hsu JL (2002) Hodgkin’s disease in Asians: incidence patterns and risk factors in population-based data. Leuk Res 26:261–269 Mack TM, Cozen W, Shibata DK et al (1995) Concordance for Hodgkin’s disease in identical twins suggesting genetic susceptibility to the young- adult form of the disease. N Engl J Med 332:413–418 Diepstra A, Niens M, Vellenga E et al (2005) Association with HLA class I in Epstein–Barr- virus-positive and with HLA class III in Epstein- Barr- virus-negative Hodgkin’s lymphoma. Lancet 365:2216–2224 Niens M, van den Berg A, Diepstra A et al (2006) The human leukocyte antigen class I region is associated with EBV-positive Hodgkin’s lymphoma: HLA-A and HLA complex group 9 are putative candidate genes. Cancer Epidemiol Biomark Prev 15:2280–2284 Enciso-Mora V, Broderick PMY et al (2010) A genome-wide association study of Hodgkin’s lymphoma identifies new susceptibility loci at 2p16.1 (REL), 8q24.21 and 10p14 (GATA3). Nat Genet 42:1126–1130 Urayama KY, Jarrett RF, Hjalgrim H et al (2012) Genome-wide association study of classical Hodgkin lymphoma and Epstein-Barr virus status- defined subgroups. J Natl Cancer Inst 104:240–253 Cozen W, Li D, Best T et al (2012) A genome- wide meta-analysis of nodular sclerosing Hodgkin lymphoma identifies risk loci at 6p21.32. Blood 119:469–475 4 Microenvironment, Cross-Talk, and Immune Escape Mechanisms 87. Sud A, Thomsen H, Orlando G et al (2018) Genome- wide association study implicates immune dysfunction in the development of Hodgkin lymphoma. Blood 132:1212–1218 88. Levitskaya J, Coram M, Levitsky V et al (1995) Inhibition of antigen processing by the internal repeat region of the Epstein–Barr virus nuclear antigen-1. Nature 375:685–688 89. Meij P, Leen A, Rickinson AB et al (2002) Identification and prevalence of CD8(+) T-cell responses directed against Epstein–Barr virus- encoded latent membrane protein 1 and latent membrane protein 2. Int J Cancer 99:93–99 90. Bollard CM, Aguilar L, Straathof KC et al (2004) Cytotoxic T lymphocyte therapy for EpsteinBarr virus+ Hodgkin’s disease. J Exp Med 200:1623–1633 91. Lucas KG, Salzman D, Garcia A et al (2004) Adoptive immunotherapy with allogeneic Epstein– Barr virus (EBV)-specific cytotoxic T-lymphocytes for recurrent EBV-positive Hodgkin disease. Cancer 100:1892–1901 92. Bollard CM, Gottschalk S, Torrano V et al (2014) Sustained complete responses in patients with lymphoma receiving autologous cytotoxic T lymphocytes targeting Epstein-Barr virus latent membrane proteins. J Clin Oncol 32:798–808 93. Niens M, Jarrett RF, Hepkema B et al (2007) HLA- A∗02 is associated with a reduced risk and HLA- A∗01 with an increased risk of developing EBV+ Hodgkin lymphoma. Blood 110:3310–3315 94. Jones K, Wockner L, Brennan RM et al (2016) The impact of HLA class I and EBV latency-II antigen-specific CD8+ T cells on the pathogenesis of EBV+ Hodgkin lymphoma. Clin Exp Immunol 183:206–220 95. Diepstra A, van Imhoff GW, Karim-Kos HE et al (2007) HLA class II expression by Hodgkin Reed- Sternberg cells is an independent prognostic factor in classical Hodgkin’s lymphoma. J Clin Oncol 25:3101–3108 96. Nijland M, Veenstra RN, Visser L et al (2017) HLA dependent immune escape mechanisms in B-cell lymphomas: implications for immune checkpoint inhibitor therapy? Oncoimmunology e1295202:6 97. Reichel J, Chadburn A, Rubinstein PG et al (2015) Flow sorting and exome sequencing reveal the oncogenome of primary Hodgkin and Reed- Sternberg cells. Blood 125:1061–1072 98. Diepstra A, Poppema S, Boot M et al (2008) HLA-G protein expression as a potential immune escape mechanism in classical Hodgkin’s lymphoma. Tissue Antigens 71:219–226 99. Zocchi MR, Catellani S, Canevali P et al (2012) High ERp5/ADAM10 expression in lymph node microenvironment and impaired NKG2D ligands recognition in Hodgkin lymphomas. Blood 119:1479–1489 100. Steidl C, Shah SP, Woolcock BW et al (2011) MHC class II transactivator CIITA is a recurrent 101. 102. 103. 104. 105. 106. 107. 108. 109. 110. 111. 112. 113. 114. 85 gene fusion partner in lymphoid cancers. Nature 471:377–383 Walunas TL, Lenschow DJ, Bakker CY et al (1994) CTLA-4 can function as a negative regulator of T cell activation. Immunity 1:405–413 Alegre M, Frauwirth KA (2001) Thompson CB. T cell regulation by CD28 and CTLA-4. Nat Rev Immunol 1:220–228 Bashey A, Medina B, Corringham S et al (2009) CTLA-4 blockade with ipilimumab to treat relapse of malignancy after allogeneic hematopoietic cell transplantation. Blood 113:1581–1588 Davids MS, Kim HT, Bachireddy P et al (2016) Ipilimumab for patients with relapse after allogeneic transplantation. N Engl J Med 375:143–153 Yamamoto R, Nishikori M, Kitawaki T et al (2008) PD-1-PD-1 ligand interaction contributes to immunosuppressive microenvironment of Hodgkin lymphoma. Blood 15(111):3220–3224 Vari F, Arpon D, Keane C et al (2018) Immune evasion via PD-1/PD-L1 on NK-cells and monocytes/ macrophages is more prominent in Hodgkin lymphoma than DLBCL. Blood 131:1809–1819 Green MR, Monti S, Rodig SJ et al (2010) Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell. Blood 116:3268–3277 Ansell SM, Lesokhin AM, Borrello I et al (2015) PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med 372:311–319 Armand P, Engert A, Younes A et al (2018) Nivolumab for relapsed/refractory classical Hodgkin lymphoma after failure of autologous hematopoietic cell transplantation: extended follow-up of the multicohort single-arm phase II CheckMate 205 trial. J Clin Oncol 36:1428–1439 Younes A, Santoro A, Shipp M et al (2016) Nivolumab for classical Hodgkin’s lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol 17:1283–1294 Chen R, Zinzani PL, Fanale MA et al (2017) Phase II study of the efficacy and safety of pembrolizumab for relapsed/refractory classic Hodgkin lymphoma. J Clin Oncol 35:2125–2132 Tumeh PC, Harview CL, Yearley JH et al (2014) PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515:568–571 Carey CD, Gusenleitner D, Lipschitz M et al (2017) Topological analysis reveals a PD-L1-associated microenvironmental niche for Reed-Sternberg cells in Hodgkin lymphoma. Blood 130:2420–2430 Roemer MGM, Redd RA, Cader FZ et al (2018) Major histocompatibility complex class II and programmed death ligand 1 expression predict outcome after programmed death blockade L. Visser et al. 86 115. 116. 117. 118. 119. 120. 121. 122. 123. 124. 125. 126. 127. 128. in classical Hodgkin lymphoma. J Clin Oncol 36:942–950 Muenst S, Hoeller S, Dirnhofer S et al (2009) Increased programmed death-1+ tumor-infiltrating lymphocytes in classical Hodgkin lymphoma substantiate reduced overall survival. Hum Pathol 40:1715–1722 Goldberg MV, Drake CG (2011) LAG-3 in cancer immunotherapy. Curr Top Microbiol Immunol 344:269–278 Huard B, Prigent P, Tournier M et al (1995) CD4/ major histocompatibility complex class II interaction analyzed with CD4− and lymphocyte activation gene-3 (LAG-3)-Ig fusion proteins. Eur J Immunol 25:2718–2721 Gandhi MK, Lambley E, Duraiswamy J et al (2006) Expression of LAG-3 by tumor-infiltrating lymphocytes is coincident with the suppression of latent membrane antigen-specific CD8+ T-cell function in Hodgkin lymphoma patients. Blood 108:2280–2289 Camisaschi C, Casati C, Rini F et al (2010) LAG-3 expression defines a subset of CD4(+)CD25(high) Foxp3(+) regulatory T cells that are expanded at tumor sites. J Immunol 184:6545–6551 Duffield AS, Ascierto ML, Anders RA et al (2017) Th17 immune microenvironment in Epstein-Barr virus-negative Hodgkin lymphoma: implications for immunotherapy. Blood Adv 1:1324–1334 Wein F, Weniger MA, Höing B et al (2017) Complex immune evasion strategies in classical Hodgkin lymphoma. Cancer Immunol Res 5:1122–1132 Dukers DF, Jaspars LH, Vos W et al (2000) Quantitative immunohistochemical analysis of cytokine profiles in Epstein-Barr virus-positive and -negative cases of Hodgkin’s disease. J Pathol 190:143–149 Herbst H, Foss HD, Samol J et al (1996) Frequent expression of interleukin-10 by Epstein–Barr virus- harboring tumor cells of Hodgkin’s disease. Blood 87:2918–2929 Newcom SR, Kadin ME, Ansari AA et al (1988) L-428 nodular sclerosing Hodgkin’s cell secretes a unique transforming growth factor-beta active at physiologic pH. J Clin Invest 82:1915–1921 Newcom SR, Tagra KK (1992) High molecular weight transforming growth factor b is excreted in the urine in active nodular sclerosing Hodgkin’s disease. Cancer Res 52:6768–6773 Marshall NA, Christie LE, Munro LR et al (2004) Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma. Blood 103:1755–1762 Juszczynski P, Ouyang J, Monti S et al (2007) The AP1-dependent secretion of galectin-1 by Reed- Sternberg cells fosters immune privilege in classical Hodgkin lymphoma. Proc Natl Acad Sci U S A 104:13134–13139 Gandhi MK, Moll G, Smith C et al (2015) Brief report Galectin-1 mediated suppression of Epstein- Barr virus—specific T-cell immunity in classic Hodgkin lymphoma. Blood 110:1326–1330 129. Maggio EM, van den Berg A, de Jong D et al (2003) Low frequency of FAS mutations in Reed-Sternberg cells of Hodgkin’s lymphoma. Am J Pathol 162:29–35 130. Choe J-Y, Yun JY, Jeon YK et al (2014) Indoleamine 2,3-dioxygenase (IDO) is frequently expressed in stromal cells of Hodgkin lymphoma and is associated with adverse clinical features: a retrospective cohort study. BMC Cancer 14:335 131. Soliman H, Mediavilla-Varela M, Antonia S (2010) Indoleamine 2,3-dioxygenase. Is i tan immune suppressor? Cancer J 16:354–359 132. Schwaller J, Tobler A, Niklaus G et al (1995) Interleukin-12 expression in human lymphomas and nonneoplastic lymphoid disorders. Blood 85:2182–2188 133. Niedobitek G, Pazolt D, Teichmann M et al (2002) Frequent expression of the Epstein-Barr virus (EBV)-induced gene, EBI3, an IL-12 p40-related cytokine, in Hodgkin and Reed-Sternberg cells. J Pathol 198:310–316 134. Steidl C, Lee T, Shah SP et al (2010) Tumor- associated macrophages and survival in classical Hodgkin’s lymphoma. N Engl J Med 362:875–885 135. Guo B, Cen H, Tan X, Ke Q (2016) Meta-analysis of the prognostic and clinical value of tumor-associated macrophages in adult classical Hodgkin lymphoma. BMC Med 14:159 136. Barros MHM, Segges P, Vera-Lozada G, Hassan R, Niedobitek G (2015) Macrophage polarization reflects T cell composition of tumor microenvironment in pediatric classical Hodgkin lymphoma and has impact on survival. PLoS One 10:1–19 137. Hollander P, Rostgaard K, Smedby KE et al (2017) An anergic immune signature in the tumor microenvironment of classical Hodgkin lymphoma is associated with inferior outcome. Eur J Haematol 100:88–97 138. Andersen MD, Kamper P, Nielsen PS et al (2016) Tumour-associated mast cells in classical Hodgkin’s lymphoma: correlation with histological subtype, other tumour-infiltrating inflammatory cell subsets and outcome. Eur J Haematol 96:252–259 139. Alvaro T, Lejeune M, Salvado MT et al (2005) Outcome in Hodgkin’s lymphoma can be predicted from the presence of accompanying cytotoxic and regulatory T cells. Clin Cancer Res 11:1467–1473 140. Kelley TW, Pohlman B, Elson P et al (2007) The ratio of Foxp3+ regulatory T cells to Granzyme B+ cytotoxic T/NK cells predicts prognosis in classical Hodgkin lymphoma and is independent of bcl-2 and MAL expression. Am J Clin Pathol 128:958–965 141. Oudejans JJ, Jiwa NM, Kummer JA et al (1997) Activated cytotoxic T cells as prognostic marker in Hodgkin’s disease. Blood 89:1376–1382 142. Alonso-Álvarez S, Vidriales MB, Caballero MD et al (2017) The number of tumor infiltrating T-cell subsets in lymph nodes from patients with Hodgkin lymphoma is associated with the outcome after first line ABVD therapy. Leuk Lymphoma 58:1144–1152 5 What Have We Learnt from Genomics and Transcriptomics in Classic Hodgkin Lymphoma Davide Rossi and Christian Steidl Contents 5.1 Introduction 87 5.2 5.2.1 5.2.2 5.2.3 5.2.4 enomics of Hodgkin and Reed-Sternberg Cells G Cytokine Signaling NF-κB Signaling PI3K/AKT/mTOR Signaling Immune Escape 88 88 89 89 90 5.3 The Transcriptome of HRS Cells 90 5.4 Microenvironment Profiling 91 5.5 Biomarker-Driven Prognostication and Risk Stratification in cHL 92 Conclusions and Future Perspective 94 5.6 References 5.1 Introduction A prominent pathological feature of cHL is the abnormal immune response represented by the abundant TME. It is thought that the majority of the immune cells in the TME are recruited by a variety of cytokines expressed by the HRS cells [1]. D. Rossi (*) Oncology Institute of Southern Switzerland, Bellinzona, Switzerland e-mail: davide.rossi@ior.usi.ch C. Steidl Department of Pathology and Laboratory Medicine, British Columbia Cancer Agency and the BC Cancer Research Centre, Vancouver, BC, Canada e-mail: CSteidl@bccancer.bc.ca 94 Cytokines are low-molecular-weight proteins with a wide variety of functions that work either in a paracrine manner to modulate the activity of surrounding cells or in an autocrine fashion to affect the cells that produce them. Furthermore, it is a widely accepted concept that the overexpression of regulatory cytokines and TGFβ leads to a microenvironment that suppresses cell-mediated immunity and in return favors HRS cell survival highlighting the bidirectional crosstalk of cells involved in the pathogenesis of HL [2]. The recent advances in HRS cell genomics and profiling the tumor microenvironment have already led to better insight into the molecular underpinnings of the disease, and we are anticipating discovery of additional clues explaining © Springer Nature Switzerland AG 2020 A. Engert, A. Younes (eds.), Hodgkin Lymphoma, Hematologic Malignancies, https://doi.org/10.1007/978-3-030-32482-7_5 87 D. Rossi and C. Steidl 88 N=80 N=34 N=10 Circulating tumor DNA (Spina et al.) Laser microdissection of Hodgkin and ReedSternberg cells (Tiacci et al.) Flow sorting of Hodgkin and Reed-Sternberg cells cells (Reichel et al.) samples 47.1 32.4 5.9 11.8 23.5 20.6 5.9 0 2.9 8.8 17.6 0 0 0 2.9 0 0 0 2.9 11.8 0 0 2.9 0 0 5.9 0 0 0 0 0 0 0 0 0 0 2.9 0 2.9 0 0 0 0 0 0 2.9 0 0 0 0 0 0 2.9 0 0 0 0 2.9 0 0 0 0 0 2.9 0 0 5.9 0 0 0 0 0 0 2.9 0 0 0 0 40 10 60 40 20 70 0 10 0 0 10 10 50 0 0 0 0 10 0 10 0 0 10 10 0 0 0 0 10 0 0 0 0 0 0 0 0 0 0 0 0 20 0 0 0 0 0 0 0 0 10 0 10 0 10 0 0 10 0 0 10 0 0 10 0 0 0 10 0 0 0 0 0 0 10 0 0 0 % of mutated samples NA 37.5 35.0 27.5 18.8 16.3 15.0 12.5 11.3 11.3 11.3 10 10 10 7.5 7.5 7.5 6.3 6.3 6.3 6.3 5 5 5 5 5 5 5 3.8 3.8 3.8 3.8 3.8 3.8 3.8 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 0 0 0 0 0 0 0 0 0 0 0 SOCS1 STAT6 TNFAIP3 ITPKB GNA13 B2M ATM SPEN KMT2D TP53 XPO1 BTG1 HIST1H1E ARID1A CD36 FBXW7 P2RY8 CIITA IKBKB NFKBIE PIK3CA BIRC3 CREBBP FBXO11 IRF8 TBL1XR1 PCBP1 TNFRSF14 BTK CD58 HIST1H1C RIPK1 TRAF3 ZMYM3 MYC BCL2 BCOR CCND3 CD79B CXCR4 EGR2 HIST1H3B ID3 IRAK1 IRF4 KLHL6 MAP2K1 MAP3K14 NOTCH1 NOTCH2 PIM1 PLCG2 POT1 S1PR2 SIN3A TET2 WHSC1 EZH2 PRDM1 EP300 BCL6 BRAF CCND1 FGFR2 KLF2 MEF2B STAT3 CARD11 CCND2 CD70 CD79A FOXO1 KRAS MYD88 NRAS RRAGC TCF3 TRAF2 Spina et al. cHL cohort Tiacci et al. cHL cohort Reichel et al. cHL cohort Not Available Mutated sample Unmutated sample Fig. 5.1 The mutational profile of newly diagnosed cHL. The heatmap shows individual non-synonymous somatic mutations detected in three different cohorts (Spine et al., green; Tiacci et al., yellow; Reichel et al., blue). Each cohort has a different source of tumor DNA (i.e., circulating tumor DNA, DNA from laser microdissected Hodgkin and Reed-Sternberg cells, and DNA from flow-sorted Hodgkin and Reed-Sternberg cells). Each row represents a gene and each column represents a primary tumor. The heatmap was manually clustered to emphasize mutational co-occurrence. Mutations are color-coded in red. The horizontal bar graph shows the gene mutation frequency found in each different cohort the unique crosstalk and symbiosis of the malignant cells with the non-malignant cells in the TME. In the following, we will highlight recent advances and future directions in (1) HRS cell genomics (Fig. 5.1) and (2) gene expression profiling. evidence that various molecular mechanisms, including gene mutations and chromosomal alterations, can converge along with deregulated surface receptor signaling to lead to exuberant activation of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway [3–5]. Chromosomal aberrations of the JAK2 locus on 9p24.1 in HRS cells were reported in one study in the large majority of cHL cases, including copy gain in 60% of cases, amplification in 30%, and polysomy in 10% [5]. Almost ubiquitous (∼90% of cases) are genetic alterations of a variety of other JAK-STAT pathway members, which goes beyond previous estimates based on the presence of copy number gains of JAK2. 5.2 enomics of Hodgkin and G Reed-Sternberg Cells 5.2.1 Cytokine Signaling Constitutive activation of cytokine signaling pathways is a long recognized molecular hallmark of HRS cells. A number of studies provided 5 What Have We Learnt from Genomics and Transcriptomics in Classic Hodgkin Lymphoma These include mutational disruption of the SOCS1 (40%) and PTPN1 (20%) negative pathway regulators, activating mutations of JAK1 (10%), and multiple STAT transcription factors (STAT6, 30%; STAT3, 10% STAT5B, 10%) [4]. The association between convergent and recurrent point mutations in genes coding for interacting proteins of the JAK-STAT pathway is a common mechanism shared by CD30+ lymphomas, in particular cHL and anaplastic large cell lymphoma. Concurrence of these multiple somatic events indicates that these synergistic mutations are strongly selected for beyond single alterations to sustain pathway activation [6]. The pervasive targeting of JAK-STAT signaling genes in cHL, along with functional genomic studies, confirmed that JAK-STAT pathway activation represents a vulnerability of cHL and makes clinically available JAK or STAT inhibitors an attractive therapeutic approach in this disease [4]. 5.2.2 NF-κB Signaling Overall, genetic lesions in the NF-κB pathway occur in most of cHL cases, confirming their important role in the pathogenesis of this disease. Genomic gains/amplifications of the NF-κB transcription factor REL have been described in about 70% of cHL cases causing protein overexpression [7]. Mutations in negative regulators of NF-κB constitute a second important mechanism of pathway activation. NFKBIA, encoding IκBα, an inhibitor that binds NF-κB factors and prevents their nuclear translocation, is mutated in about 20% of cHL [8]. NFKBIE, encoding IκBε, an inhibitor that binds NF-κB factors and prevents their nuclear translocation, has been found in 30% of cases [9]. TNFAIP3 the master negative regulator of NF-κB pathway is mutated in 30% of cases [3, 10]. Overall, NF-κB pathway mutations have been described in cHL with a higher frequency in EBV-negative cases, consistent with data establishing expression of the EBV-latent 89 membrane protein 1 (LMP-1) as an independent contributor to constitutive activation of NF-κB in cHL [11, 12]. 5.2.3 PI3K/AKT/mTOR Signaling Mutations within the PI3K/AKT/mammalian target of rapamycin (mTOR) pathway occur in 50% of cHL, consistent with the pre-clinical evidence that cHL is addicted to this actionable cellular program [13]. ITPKB is mutated in 25% of cases. ITPKB is a non-canonical antagonist of PI3K. Physiologically, ITPKB dampens PI3K/ AKT signaling by producing IP4, a soluble antagonist of the AKT-activating PI3K-product PIP3. ITPKB mutations are quite specific for cHL, being rare or absent in other lymphomas, and cause the subcellular delocalization of the mutated protein in primary HRS cells. Moreover, ITPKB mutations correlate with PI3K/AKT signaling activation at both the gene expression and protein levels and, consistent with linkages to the downstream PI3K pathway, associate with resistance to PI3K inhibitors [3, 4]. The Ga13 G-protein subunit encoded by GNA13 is mutated in 10% of cHL [3, 4]. By transmitting signals from the G-proteincoupled receptors S1PR2 and P2RY8 that result in the inhibition of AKT phosphorylation, Ga13 ensures the proper confinement of proliferating germinal center (CG) B cells within secondary lymphoid follicles and at the same time constrains their expansion by facilitating apoptosis in this potentially dangerous niche. Inactivating GNA13 mutations promote altered GC B-cell migration within and beyond the GC, as well as impaired cellular adhesion, resulting in cells that may have a reduced ability to establish interactions with GC helper cells. Under normal conditions, a GC cell that is unable to form these helper cell interactions, due to either GC exit or ineffective cellular adhesion, would undergo apoptosis. However, GNA13-mutated GC B cells are resistant to programmed cell death by leading to elevated levels of pAKT [14]. D. Rossi and C. Steidl 90 Importantly, the genomic studies of microdissected HRS cells and ctDNA strongly suggest that mutations of STAT6, TNFAIP3, GNA13, and ITPKB are preferentially occurring in the ancestral clones, indicating that they are an early event in cHL pathogenesis [3, 4]. 5.3 The Transcriptome of HRS Cells Overall, gene expression profiling experiments have contributed substantially to an improved understanding of the disease with respect to the inherent phenotypic features of the malignant HRS cells and the specific composition of the 5.2.4 Immune Escape tumor microenvironment. Furthermore, first steps could be made to establish outcome corClassical HL leverages multiple genetic mecha- relations with the potential to improve treatment nisms to escape immunosurveillance. First, reduc- outcome prediction. However, many questions tion or loss of antigen presentation through B2M remain including often contradictory results inactivating mutations/deletion has been described derived from different patient cohorts. Focusing in 30% of cases [4, 15]. B2M encodes β2 micro- on HRS cells, the first major contribution of globulin, a key component of the major histocom- gene expression profiling was made by investipatibility complex (MHC) class I which is gating HL-derived cell lines. These pivotal studrequired for its expression and antigen presenta- ies first established a transcriptome-wide view tion on the cell surface. Consistently, genetic dis- of the malignant cell compartment describing a ruption of B2M results in the loss of MHC class I unifying gene signature for cHL [22]. Together protein expression on lymphoma cells [16, 17]. with other important similar studies, this gene Second, gene rearrangements involving the expression work helped to elucidate the loss of MHC class II transactivator CIITA were found in B-cell signature phenotypes and the deregulated 15% of cases. CIITA rearrangements result in the expression of transcription factor networks in disruption of its transcriptional proprieties and comparison to the normal germinal center B-cell loss of MHC class II expression on cHL cells. counterparts [23–26]. Major advances have also Both MHC class I and MHC class II losses are been made examining microdissected HRS cells predicted to abrogate the interaction of the T-cell from clinical biopsy material that further charreceptor (TCR) with a MHC-bound antigen pre- acterized transcriptional changes in primary sented on the cell surface, which is the first signal cells [27–29]. Steidl and colleagues identified required to activate T-cell antitumor response [18]. significant phenotypic heterogeneity within Loss of both MHC I and II expression and related cHL and described for the first time genomelack of neoantigen expression have been consis- wide association with treatment outcome [28] tently found to induce “cold” immune microenvi- (Fig. 5.2). The second study by Tiacci and colronments in lymphoma and other cancers [19, 20]. leagues added significant texture to the primary Third, PD-L1 and PD-L2 overexpression HRS cell expression phenotype emphasizing the driven by copy gain of 9p24.1 is a frequent event differences in comparison to HL-derived cell in cHL. Alterations of the PD-L1 and PD-L2 loci lines [29]. Furthermore, two molecularly diswere reported to include polysomy in 5% of cHL, tinct cHL subtypes were discovered related to copy gain in 56%, and amplification in 36%. The the transcription factor activity of NOTCH1, 9p24.1 amplification in cHL acts through two MYC, and IRF4. Another study for the first time distinct mechanisms resulting in copy number- also focused on gene expression profiling of dependent increases of PD-L1 and PD-L2 expres- microdissected cells from nodular lymphocyte sion and increased JAK/STAT signaling promoted predominant Hodgkin lymphoma (NLPHL) by JAK2 protein expression which is almost describing a close relationship to classical exclusively co-regulated with PD-L1 and Hodgkin lymphoma and T-cell-rich B-cell lymPD-L2 in the 9p24.1 amplicon [21]. phoma [27]. 5 What Have We Learnt from Genomics and Transcriptomics in Classic Hodgkin Lymphoma a 91 b Cluster HRS Cell Status Histological Subtype Sample Type 3 Treatment Outcome Histological Subtype HRS Cell Status Sample Type 4 2 2 1 0 0 -1 -2 -2 Residual B-cell Signature Receptor Signaling Signature Cluster -4 -8 IGL AMIGO2 IGJ IGLJ3 HLA-C IGHG3 -12 POU2AF1 PERP RANK 0 TGFBR3 IL9 IL26 CCND2 TFPI2 Fold Change 200 150 100 50 0 CCL17 Fold Change C1QB GZMB CXCL10 Fold Change Cytotoxic Signature 20 15 10 5 0 HRS Cell Status Germinal Centre EBV Positive Cluster A EBV Negative Cluster B Not determined Cluster C Histological Subtype Sample Type Nodular Sclerosis Diagnosis Mixed Cellularity Relapse Treatment Outcome Treatment Success Treatment Failure GrB Immunohistochemistry RANK (TNFRSF11A) Immunohistochemistry Fig. 5.2 Expression profiling of 29 samples of microdissected Hodgkin and Reed-Sternberg cells. (a) Unsupervised hierarchical clustering of gene expression profiles is shown using high variance genes. Red indicates relative overexpression and green relative under-expression. Patient clusters, histological subtype, EBV positivity of HRS cells by EBER in situ hybridization, and sample type are shown. The average fold changes of genes representative of the three main signatures are shown in the bar plots. Representative immunohistochemistry images are depicted demonstrating cytoplasmic positivity of Granzyme B (GrB, black arrows) and RANK in HRS cells. (b) Unsupervised hierarchical clustering of the cohort using the most differentially expressed genes between primary treatment failure and success. Treatment outcome, histological subtype, EBV positivity of HRS cells by EBER in situ hybridization, and sample type are shown. Cases cluster according to the outcome groups (two main clusters) 5.4 ment [30–33]. However, some of these data provide evidence that at least parts of the apparent signatures are derived from HRS cells [31, 33]. In one study a specific gene expression signature could be linked to EBV positivity with genes overexpressed indicative of an increased Th1/ antiviral response in comparison to the EBV- negative cases [32]. In addition to a better characterization of certain Hodgkin lymphoma subtypes Microenvironment Profiling Focusing on the HL microenvironment, a number of genome-wide gene expression studies have been published to date analyzing whole tissue lymph node biopsy material. Since the HRS cells are largely outnumbered by reactive cells in most biopsies, these studies on whole frozen biopsies are regarded as a reflection of the microenviron- D. Rossi and C. Steidl 92 two chemotherapy courses has prognostic implications. A drop of 100-fold or 2-log drop in ctDNA after two chemotherapy courses, a threshold proposed and validated also in DLBCL, associates with complete response and 5.5 Biomarker-Driven cure in advanced-stage cHL treated with ABVD [3]. Conversely, a drop of less than 2-log in Prognostication and Risk ctDNA after two ABVD courses associates with Stratification in cHL progression and inferior survival. Quantification The lack of extensive genotyping of microdis- of ctDNA complements interim PET/CT in sected HRS cells from large cHL patient cohorts determining residual disease. Indeed, cured has so far limited the identification of mutations patients who are inconsistently judged as affecting cHL outcome. ctDNA has been estab- interim PET/CT positive have a >2-log drop in lished as a source of tumor DNA for cHL muta- ctDNA, while relapsing patients who are incontional profiling. By overcoming the major sistently judged as interim PET/CT negative technical hurdles that have so far limited cHL have a <2-log drop in ctDNA. On this basis, genotyping, ctDNA technology will allow large- incorporation of both PET/CT and ctDNA monscale assessment of mutations in different clini- itoring into clinical trials should allow to precal phases ranging from newly diagnosed to cisely define their cumulative sensitivity and refractory disease, and longitudinally during dis- specificity in anticipating the clinical course of ease treatment, which in turn can reveal yet cHL patients. Indeed, though interim PET/CT unknown prognostic and predictive biomarkers response assessment is a novel approach to for cHL [3] (Fig. 5.3). refine management strategies before completing Beside disclosing tumor mutation profiles, treatment in cHL, meta-analyses demonstrated a ctDNA can also provide an estimate of the lev- certain degree of inaccuracy of this application. els of residual disease during treatment in In order to fill this gap, an area of growing intercHL. Consistently, ctDNA quantification after est is pairing interim PET/CT with biomarkers, Log fold change in tumor ctDNA defined by specific gene signatures, these experiments also allowed for the study of outcome correlations using supervised analyses. 1 0 Nodular sclerosis cHL (NSCHL) Mixed cellularity cHL (MCCHL) Lymphocyte rich cHL (LRCHL) -1 -2 -3 iPET positive – Progressive disease iPET positive – Cured iPET negative – Progressive disease iPET negative – Cured -4 ND 3 4 4 3 3 3 3 1 2 2 2 4 4 5 4 1 2 1 1 1 1 1 3 1 PD PD PD PD PD PD CR CR CR CR CR CR CR CR CR CR CR CR CR CR CR CR CR CR Fig. 5.3 Change in tumor ctDNA is a prognostic biomarker in cHL treated with chemotherapy. Waterfall plot of the log-fold change in ctDNA load after two courses of ABVD in 24 advanced-stage cHL cases. At the bottom of the graph, the interim PET/CT response scored according to the Deauville criteria, and the final outcome of the patient is indicated. Histological subtype of cHL is shown Deauville score Outcome above the plot. Each column is color-coded according to the interim PET/CT results and the final patient outcome. Levels of ctDNA are normalized to baseline levels. The dashed line tracks the −2-log threshold (iPET interim PET/CT, ND not detectable, PD progressive disease, CR complete remission and cure) 5 What Have We Learnt from Genomics and Transcriptomics in Classic Hodgkin Lymphoma such as ctDNA or serum TARC, to enhance their cumulative predictive value. The type of 9p24.1 chromosomal aberration affects cHL outcome in both chemotherapy and immunotherapy treatment settings. Among chemotherapy- treated cHL, 9p24.1 amplification, but not polysomy or copy gain, associates with inferior progression-free survival [21]. Among patients treated with checkpoint blockade antibodies, those with higher-level 9p24.1 alterations and PD-L1 expression on HRS cells had superior PFS [34]. These analyses highlight the importance of quantifying and specifically delineating PD-L1 expression in malignant HRS cells for prognostic purposes. Beside genetics, the tumor/TME phenotype has been prominently involved in past and ongoing biomarker considerations in cHL. Studies have used dichotomized clinical data sets based on slightly different definitions of clinical extremes according to the outcome after systemic treatment (i.e., treatment success versus treatment failure). However, these types of analyses have in part yielded conflicting results regarding the specific signatures that best define these clinical extremes. While one study found overexpression of genes involved in fibroblast activation, angiogenesis, extracellular matrix remodeling, and downregulation of tumor suppressor genes to be linked with an unfavorable prognosis, another study found a correlation of fibroblast activation, fibroblast chemotaxis, and matrix remodeling with improved outcome [30, 31]. While small sample sizes in both studies might have hampered interpretation, a more recent study investigated gene expression profiles of 130 patients including 38 patients whose primary treatments failed [33]. This study validated previously reported outcome correlations and furthermore showed that a gene signature of macrophages was linked to primary treatment failure. In a number of immunohistochemistry-based followup studies, multiple groups demonstrated that the enumeration of CD68+ macrophages in lymph node biopsies was a strong and independent predictor of disease-specific survival [35]. Specifically, an elegant retrospective study using Intergroup E2496 trial material (comparing 93 ABVD to the Stanford V regimen) showed that high abundance of both CD68+ and CD163+ cells was correlated with shorter progression-free and overall survival independent of the IPS [36]. Importantly, the latter study used a computer- based scoring algorithm (Aperio) and systematically derived scoring thresholds that were tested in an independent validation cohort. Maximizing the concept of combining markers for building outcome predictors, a recent study used the same E2496 trial material to train a predictive model using intermediate density digital gene expression profiling developed in and applicable to routinely collected formalin-fixed paraffin-embedded tissue [37]. In this study the authors developed a 23-gene predictive model and associated thresholds to distinguish high-risk from low-risk advanced-stage Hodgkin lymphoma using overall survival as the end point. Encouragingly, when applied to an independent cohort treated with ABVD chemotherapy, the model validated the results in the E2496 training cohort identifying the patient at high risk of death. Follow-up studies are needed to further validate and implement biomarker assays for potential routine clinical use, risk stratification, and assessment as a predictive biomarker possibly guiding initial treatment decisions. To date, cHL research has been for the most part focused on primary specimens, and only a few studies have explored the biology of relapse. However recently, the feasibility of biomarker studies and assay development at the time point of relapse was demonstrated in the context of outcome prediction of salvage therapy and ASCT [38]. The authors demonstrated that gene expression patterns, reflecting TME composition, differ significantly between matched primary and relapse specimens in a subset of cHL patients. Based on the superior predictive properties of gene expression measurements in relapse specimens, a novel clinically applicable prognostic model/assay (RHL30) was developed that identifies a subset of patients at high risk of treatment failure following salvage therapy and ASCT. Specifically, RHL30 identifies a high-risk group of patients with significantly inferior post-ASCT-FFS compared to the low- D. Rossi and C. Steidl 94 risk group (5-year: 23.8% high-risk vs. 77.5% low-risk) and also inferior post-ASCT-OS (5-year: 28.7% high-risk vs. 85.4% low-risk). Importantly, the prognostic power of RHL30 was reproduced in two separate validation cohorts of relapse specimens, and the RHL30 was statistically independent of all previously described prognostic markers in the validation cohorts, including post-salvage therapy response assessment by PET/CT [38]. 5.6 Conclusions and Future Perspective The advent of next-generation sequencing has significantly added to the armamentarium of genomics techniques interrogating tumor genetics of cHL and elucidating the molecular underpinnings of the unique crosstalk of the malignant HRS cells with their immune microenvironment. The sequencing studies of ctDNA and enrichment of HRS cells confirmed the importance of, and added texture to, the known molecular hallmarks of NFκB, JAK-STAT, and PI3K signaling as well as immune privilege phenotypes. Moreover, gene expression profiling studies of the microenvironment have reached more maturity in comprehensively describing cellular compartments in the TME and validated key correlations to pathologic and clinical outcome data. In particular, effective biomarker assay translation appears more and more realistic with the emergence of methods that are compatible with FFPE tissues that can be applied to relapse biopsies and are minimally invasive (e.g., serial peripheral blood draws) for dynamic biomarker testing. Despite these most recent advances, a number of challenges and open questions remain that need to be addressed in future studies. First, with respect to cHL biology, no unique and specific somatic gene mutations have been identified that would explain the unique histopathology of cHL in contrast to other lymphomas, leaving room for future discoveries. Second, systematic integration of HRS cell genomics with features and cellular components of the TME are lacking. Third, sample numbers for genomic landscape studies are still limited to be fully powered for mutational pattern analysis and robust outcome correlates in patients treated with standard of care. Finally, with the emergence of targeted therapies (e.g., brentuximab vedotin [39]) and modern immunotherapies (e.g., checkpoint inhibitors [40] or bispecific antibodies [41]), predictive biomarker development using genomics has to be prioritized alongside the next generation of clinical trials and population-based outcome studies of patients receiving these novel therapies in the standard of care setting. Excitingly, novel cutting-edge genomics techniques might also overcome some of the described obstacles, including HRS cell sequencing, to interrogate the non-coding space (e.g., whole genome sequencing), epigenetic profiling (e.g., ATAC-seq, bisulfite sequencing), and RNAseq at the single cell level to characterize the TME. Integrating these novel genomics approaches for dynamic, multi-time point biomarker testing alongside existing and novel therapeutic approaches holds the great promise to fully realize the benefits of precision medicine by genomics-driven clinical decision-making. References 1. Kuppers R (2009) The biology of Hodgkin's lymphoma. Nat Rev Cancer 9(1):15–27 2. Steidl C, Connors JM, Gascoyne RD (2011) Molecular pathogenesis of Hodgkin’s lymphoma: increasing evidence of the importance of the microenvironment. J Clin Oncol 29(14):1812–1826 3. Spina V, Bruscaggin A, Cuccaro A, Martini M, Di Trani M, Forestieri G et al (2018) Circulating tumor DNA reveals genetics, clonal evolution, and residual disease in classical Hodgkin lymphoma. Blood 131(22):2413–2425 4. Tiacci E, Ladewig E, Schiavoni G, Penson A, Fortini E, Pettirossi V et al (2018) Pervasive mutations of JAK-STAT pathway genes in classical Hodgkin lymphoma. Blood 131(22):2454–2465 5. Roemer MG, Advani RH, Redd RA, Pinkus GS, Natkunam Y, Ligon AH et al (2016) Classical Hodgkin lymphoma with reduced beta2M/MHC class I expression is associated with inferior outcome independent of 9p24.1 status. Cancer Immunol Res 4(11):910–916 6. Crescenzo R, Abate F, Lasorsa E, Tabbo F, Gaudiano M, Chiesa N et al (2015) Convergent mutations and kinase fusions lead to oncogenic STAT3 activation in anaplastic large cell lymphoma. Cancer Cell 27(4):516–532 5 What Have We Learnt from Genomics and Transcriptomics in Classic Hodgkin Lymphoma 7. Joos S, Menz CK, Wrobel G, Siebert R, Gesk S, Ohl S et al (2002) Classical Hodgkin lymphoma is characterized by recurrent copy number gains of the short arm of chromosome 2. Blood 99(4):1381–1387 8. Lake A, Shield LA, Cordano P, Chui DT, Osborne J, Crae S et al (2009) Mutations of NFKBIA, encoding IkappaBalpha, are a recurrent finding in classical Hodgkin lymphoma but are not a unifying feature of non-EBV-associated cases. Int J Cancer 125:1334 9. Emmerich F, Theurich S, Hummel M, Haeffker A, Vry MS, Dohner K et al (2003) Inactivating I kappa B epsilon mutations in Hodgkin/Reed-Sternberg cells. J Pathol 201(3):413–420 10. Schmitz R, Hansmann ML, Bohle V, Martin-Subero JI, Hartmann S, Mechtersheimer G et al (2009) TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin lymphoma and primary mediastinal B cell lymphoma. J Exp Med 206(5):981–989 11. Schumacher MA, Schmitz R, Brune V, Tiacci E, Doring C, Hansmann ML et al (2010) Mutations in the genes coding for the NF-kappaB regulating factors IkappaBalpha and A20 are uncommon in nodular lymphocyte-predominant Hodgkin's lymphoma. Haematologica 95(1):153–157 12. Etzel BM, Gerth M, Chen Y, Wunsche E, Facklam T, Beck JF et al (2017) Mutation analysis of tumor necrosis factor alpha-induced protein 3 gene in Hodgkin lymphoma. Pathol Res Pract 213(3):256–260 13. Johnston PB, Pinter-Brown LC, Warsi G, White K, Ramchandren R (2018) Phase 2 study of everolimus for relapsed or refractory classical Hodgkin lymphoma. Exp Hematol Oncol 7:12 14. Muppidi JR, Schmitz R, Green JA, Xiao W, Larsen AB, Braun SE et al (2014) Loss of signalling via Galpha13 in germinal centre B-cell-derived lymphoma. Nature 516(7530):254–258 15. Reichel J, Eng K, Elemento O, Cesarman E, Roshal M (2013) Exome sequencing of purified Hodgkin Reed- Sternberg cells reveals recurrent somatic mutations in genes responsible for antigen presentation, chromosome integrity, transcriptional regulation and protein ubiquitination. Blood 122(21):625 16. Liu Y, Abdul Razak FR, Terpstra M, Chan FC, Saber A, Nijland M et al (2014) The mutational landscape of Hodgkin lymphoma cell lines determined by wholeexome sequencing. Leukemia 28(11):2248–2251 17. Challa-Malladi M, Lieu YK, Califano O, Holmes AB, Bhagat G, Murty VV et al (2011) Combined genetic inactivation of beta2-microglobulin and CD58 reveals frequent escape from immune recognition in diffuse large B cell lymphoma. Cancer Cell 20(6):728–740 18. Steidl C, Shah SP, Woolcock BW, Rui L, Kawahara M, Farinha P et al (2011) MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers. Nature 471(7338):377–381 19. Ennishi D, Takata K, Beguelin W, Duns G, Mottok A, Farinha P et al (2019) Molecular and genetic characterization of MHC deficiency identifies EZH2 as therapeutic target for enhancing immune recognition. Cancer Discov 9(4):546–563 95 20. Grasso CS, Giannakis M, Wells DK, Hamada T, Mu XJ, Quist M et al (2018) Genetic mechanisms of immune evasion in colorectal Cancer. Cancer Discov 8(6):730–749 21. Roemer MG, Advani RH, Ligon AH, Natkunam Y, Redd RA, Homer H et al (2016) PD-L1 and PD-L2 genetic alterations define classical Hodgkin lymphoma and predict outcome. J Clin Oncol 34:2690 22. Kuppers R, Klein U, Schwering I, Distler V, Brauninger A, Cattoretti G et al (2003) Identification of Hodgkin and Reed-Sternberg cell-specific genes by gene expression profiling. J Clin Invest 111(4):529–537 23. Schwering I, Brauninger A, Klein U, Jungnickel B, Tinguely M, Diehl V et al (2003) Loss of the B-lineage-specific gene expression program in Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma. Blood 101(4):1505–1512 24. Mathas S, Janz M, Hummel F, Hummel M, Wollert- Wulf B, Lusatis S et al (2006) Intrinsic inhibition of transcription factor E2A by HLH proteins ABF-1 and Id2 mediates reprogramming of neoplastic B cells in Hodgkin lymphoma. Nat Immunol 7(2):207–215 25. Stein H, Marafioti T, Foss HD, Laumen H, Hummel M, Anagnostopoulos I et al (2001) Down-regulation of BOB.1/OBF.1 and Oct2 in classical Hodgkin disease but not in lymphocyte predominant Hodgkin disease correlates with immunoglobulin transcription. Blood 97(2):496–501 26. Jundt F, Kley K, Anagnostopoulos I, Schulze Probsting K, Greiner A, Mathas S et al (2002) Loss of PU.1 expression is associated with defective immunoglobulin transcription in Hodgkin and Reed- Sternberg cells of classical Hodgkin disease. Blood 99(8):3060–3062 27. Brune V, Tiacci E, Pfeil I, Doring C, Eckerle S, van Noesel CJ et al (2008) Origin and pathogenesis of nodular lymphocyte-predominant Hodgkin lymphoma as revealed by global gene expression analysis. J Exp Med 205(10):2251–2268 28. Steidl C, Diepstra A, Lee T, Chan FC, Farinha P, Tan K et al (2012) Gene expression profiling of microdissected Hodgkin Reed-Sternberg cells correlates with treatment outcome in classical Hodgkin lymphoma. Blood 120(17):3530–3540 29. Tiacci E, Doring C, Brune V, van Noesel CJ, Klapper W, Mechtersheimer G et al (2012) Analyzing primary Hodgkin and Reed-Sternberg cells to capture the molecular and cellular pathogenesis of classical Hodgkin lymphoma. Blood 120(23):4609–4620 30. Devilard E, Bertucci F, Trempat P, Bouabdallah R, Loriod B, Giaconia A et al (2002) Gene expression profiling defines molecular subtypes of classical Hodgkin’s disease. Oncogene 21(19):3095–3102 31. Sanchez-Aguilera A, Montalban C, de la Cueva P, Sanchez-Verde L, Morente MM, Garcia-Cosio M et al (2006) Tumor microenvironment and mitotic checkpoint are key factors in the outcome of classic Hodgkin lymphoma. Blood 108(2):662–668 96 32. Chetaille B, Bertucci F, Finetti P, Esterni B, Stamatoullas A, Picquenot JM et al (2009) Molecular profiling of classical Hodgkin lymphoma tissues uncovers variations in the tumor microenvironment and correlations with EBV infection and outcome. Blood 113(12):2765–3775 33. Steidl C, Lee T, Shah SP, Farinha P, Han G, Nayar T et al (2010) Tumor-associated macrophages and survival in classic Hodgkin's lymphoma. N Engl J Med 362(10):875–885 34. Roemer MGM, Redd RA, Cader FZ, Pak CJ, Abdelrahman S, Ouyang J et al (2018) Major histocompatibility complex class II and programmed death ligand 1 expression predict outcome after programmed death 1 blockade in classic Hodgkin lymphoma. J Clin Oncol 36(10):942–950 35. Steidl C, Farinha P, Gascoyne RD (2011) Macrophages predict treatment outcome in Hodgkin’s lymphoma. Haematologica 96(2):186–189 36. Tan KL, Scott DW, Hong F, Kahl BS, Fisher RI, Bartlett NL et al (2012) Tumor-associated macrophages predict inferior outcomes in classic Hodgkin lymphoma: a correlative study from the E2496 intergroup trial. Blood 120(16):3280–3287 D. Rossi and C. Steidl 37. Scott DW, Chan FC, Hong F, Rogic S, Tan KL, Meissner B et al (2013) Gene expression-based model using formalin-fixed paraffin-embedded biopsies predicts overall survival in advanced-stage classical hodgkin lymphoma. J Clin Oncol 31(6):692–700 38. Chan FC, Mottok A, Gerrie AS, Power M, Nijland M, Diepstra A et al (2017) Prognostic model to predict post-autologous stem-cell transplantation outcomes in classical Hodgkin lymphoma. J Clin Oncol 35(32):3722–3733 39. Connors JM, Jurczak W, Straus DJ, Ansell SM, Kim WS, Gallamini A et al (2018) Brentuximab Vedotin with chemotherapy for stage III or IV Hodgkin’s lymphoma. N Engl J Med 378(4):331–344 40. Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M et al (2015) PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med 372(4):311–319 41. Rothe A, Sasse S, Topp MS, Eichenauer DA, Hummel H, Reiners KS et al (2015) A phase 1 study of the bispecific anti-CD30/CD16A antibody construct AFM13 in patients with relapsed or refractory Hodgkin lymphoma. Blood 125(26):4024–4031 Part II Diagnosis and First-Line Treatment 6 Clinical Evaluation James O. Armitage and Jonathan W. Friedberg Contents 6.1 Presenting Manifestations 6.2 Physical Findings and Laboratory Abnormalities 101 6.3 Pathologic Diagnosis: The Biopsy 101 6.4 Staging Systems for Hodgkin Lymphoma 103 6.5 Imaging Evaluation of the Extent of Disease 106 6.6 Clinical Evaluation During Therapy 107 6.7 Definition of the Response to Treatment 107 6.8 Complete Remission 107 6.9 Follow-Up Management 108 6.10 Conclusion 108 References 6.1 Presenting Manifestations Hodgkin lymphoma can come to clinical attention in a variety of ways. These include symptoms caused by a growing mass and systemic symptoms that are presumably cytokine induced, and a diagnosis can be made incidentally as part of an evaluJ. O. Armitage (*) Division of Hematology/Oncology, Nebraska Medical Center, Omaha, NE, USA e-mail: joarmita@unmc.edu J. W. Friedberg Wilmot Cancer Institute, University of Rochester, Rochester, NY, USA 99 108 ation for an unrelated problem. By far the most common presentation of Hodgkin lymphoma is the enlargement of lymph nodes that is typically painless and progressive. Although the most common place for lymph nodes to be found is in the neck and supraclavicular region, any lymph node-bearing area can be involved. Patients typically find enlarged nodes above the clavicle and seek medical attention when they do not regress, while physicians are relatively more likely to discover lymph nodes in other areas as part of a physical examination. Mediastinal lymphadenopathy is a particularly common finding in young women with Hodgkin lymphoma. This might be found incidentally on a chest X-ray or can be symptomatic. © Springer Nature Switzerland AG 2020 A. Engert, A. Younes (eds.), Hodgkin Lymphoma, Hematologic Malignancies, https://doi.org/10.1007/978-3-030-32482-7_6 99 100 Although unusual, patients with Hodgkin lymphoma can present with superior vena cava syndrome, but chest pain, cough, and shortness of breath are more common symptoms caused by a large mediastinal mass. Lymphadenopathy found only below the diaphragm is more common in males and in elderly patients. Mesenteric lymphadenopathy is unusual in Hodgkin lymphoma. Retroperitoneal lymphadenopathy can be painful, but is more commonly asymptomatic and found on a staging evaluation or as part of the investigation to explain system symptoms such as fever, night sweats, or weight loss. Epitrochlear lymph node involvement is unusual in Hodgkin lymphoma. Hodgkin lymphoma can involve essentially any organ in the body as either a site of presentation or by spread from lymphatic involvement. However, extranodal presentation of Hodgkin lymphoma is unusual. The most common sites to be involved are the spleen, liver, lungs, pleura, and bone marrow, although Hodgkin lymphoma confined to these sites is rare. Hodgkin lymphoma can rarely present in unusual extranodal sites. Primary CNS [1] and cutaneous [2] Hodgkin lymphoma are rare but well described. Perianal presentations are seen more commonly in patients with HIV infection. Gastrointestinal system, bone, genitourinary system, and other unusual sites are extremely rare but have been described. Bone involvement can be seen as an “ivory vertebrae,” i.e., a densely sclerotic vertebrae [3]. By far the most common systemic symptoms that occur as the presenting manifestations of Hodgkin lymphoma are fevers, night sweats, weight loss, pruritus, and fatigue. These occur in a minority of patients but can present diagnostic challenges. Hodgkin lymphoma is one of the illnesses that can cause fever of unknown origin. Occasionally the fevers of Hodgkin lymphoma occur intermittently with several days of fevers alternating with afebrile periods. This is the Pel- Ebstein fever [4, 5] that is rare, but typically occurs in the evening. Fevers from Hodgkin lymphoma can be prevented with nonsteroidal anti- inflammatory drugs such as naproxen [6]. The presence of drenching night sweats (i.e., as opposed to dampness of the head and neck) J. O. Armitage and J. W. Friedberg and unexplained weight loss are both characteristics of Hodgkin lymphoma and, along with fever, are associated with a poor prognosis. Pruritus can be the presenting manifestation of Hodgkin lymphoma. Such patients sometimes have severely excoriated skin and sometimes have been diagnosed as having neurodermatitis. Patients who present with refractory pruritus are often grateful to find the explanation of their symptoms which usually disappear with the initiation of therapy. As with other lymphomas, fatigue can be an important, although nonspecific, symptom and also usually improves with therapy. There are many unusual, but welldescribed, presentations for Hodgkin lymphoma. One rare but very characteristic presentation is alcohol-induced pain [7, 8]. The pain typically begins soon after drinking alcohol and occurs primarily in areas of involvement by lymphoma. The pain can be quite severe and last for variable periods of time. Patients with the symptom have often discontinued alcohol before the diagnosis of Hodgkin lymphoma, and to elicit the symptom often requires specific questioning by the physician. Patients can present with Hodgkin lymphoma involving the skin, but cutaneous abnormalities are more often paraneoplastic phenomenon. These can include erythema nodosum [9]; ichthyosiform atrophy [10]; acrokeratosis paraneoplastica [11]; granulomatous slack skin [12]; nonspecific urticarial, vesicular, and bullous lesions [13]; and others. A variety of other unusual presentations of Hodgkin lymphoma have been reported. Patients can present with nephrotic syndrome [14], symptoms of hypercalcemia [15–17], jaundice due to cholestasis without involvement of the liver by the lymphoma, and the “vanishing bile duct syndrome” [18, 19]. Hodgkin lymphoma very rarely presents with a primary tumor in the CNS causing the symptoms of a brain tumor characteristic of the site of involvement. Other neurological manifestations that can be present at the diagnosis of Hodgkin lymphoma involve a variety of paraneoplastic syndromes. These include paraneoplastic 6 Clinical Evaluation cerebellar degeneration [20], which typically presents with ataxia, dysarthria, nystagmus, and diplopia. The symptoms may precede the diagnosis of Hodgkin lymphoma by many months. Hodgkin lymphoma can, of course, present with spinal cord compression from retroperitoneal and osseous tumors. Other rare manifestations include limbic encephalitis (i.e., which presents with memory loss and amnesia), peripheral neuropathy, and others. 6.2 Physical Findings and Laboratory Abnormalities By far the most common physical findings in Hodgkin lymphoma are enlarged lymph nodes that might be in any lymph node-bearing area. The lymph nodes are typically firm (i.e., “rubbery”) and vary from barely palpable to large masses. However, almost any aspect of the physical examination can be made abnormal by the presence of Hodgkin lymphoma. This might include icterus, involvement of Waldeyer’s ring, findings of superior vena cava syndrome, a sternal or suprasternal mass from tumor growing out of the mediastinum, findings of a pleural effusion or pericardial fusion, an intra-abdominal mass, hepatomegaly or splenomegaly, skin involvement, and, rarely, cutaneous or neurological abnormalities. Almost any laboratory test can be abnormal at the time of diagnosis of Hodgkin lymphoma, but certain tests are characteristic and should be specifically evaluated. Patients can have leukocytosis or leukopenia. Neutrophilia and lymphopenia are sometimes seen and can confer a poor prognosis. Eosinophilia can be found incidentally before the diagnosis of Hodgkin lymphoma, and Hodgkin lymphoma should always be included in the differential diagnosis of unexplained eosinophilia [21]. In some cases, the explanation of the eosinophilia is related to production of interleukin-5 by the tumor cells [22, 23]. The most common hematological manifestation of Hodgkin lymphoma is anemia. The most 101 usual explanation seems to be a normocytic anemia associated with the presence of the tumor that resolves after therapy. However, patients can also have autoimmune hemolytic anemia [24] and a microangiopathic hemolytic anemia as part of the syndrome of thrombotic thrombocytopenic purpura has been reported. Patients can present with thrombocytopenia for a variety of reasons including hypersplenism and bone marrow involvement. However, idiopathic thrombocytopenic purpura can be a presenting manifestation of the disease [25]. Other rare hematological manifestations of Hodgkin lymphoma have included autoimmune neutropenia [26], hemophagocytic syndrome [27], coagulation factor deficiencies [28], and unexplained microcytosis [29]. Routine chemistry screening should be done in patients with Hodgkin lymphoma and might reveal renal or hepatic dysfunction, protein abnormalities, hypercalcemia, and hyperuricemia. Elevated erythrocyte sedimentation rate and C-reactive protein are frequently seen and have been associated with a poor prognosis. 6.3 Pathologic Diagnosis: The Biopsy The oncologist must be certain that the Hodgkin lymphoma diagnosis was based on an adequate biopsy specimen that was examined using appropriate morphologic and immunohistochemical criteria. Whole lymph node excision is preferable for pathologic examination. The pathologic diagnosis of Hodgkin lymphoma is fully discussed in Chap. 3. The site of biopsy must be determined with the radiologist and surgeon. In general, the largest abnormal peripheral lymph node should be excised. If a fluorine-18-deoxyglucose positron emission tomography (FDG-PET) has been performed, the patient should be biopsied in the most avid site to avoid a partially necrotic zone. If there are only deep nodes, the following types of biopsy can be proposed. A thoracoscopic or laparoscopic approach under general J. O. Armitage and J. W. Friedberg 102 anesthesia with, if necessary, preoperative localization to facilitate resection can be performed [30]. Image-guided core needle biopsy is increasingly used and has a rising success rate of more than 90% [31–33]. However, the method has the disadvantage of only permitting relatively small biopsies. In addition, this type of biopsy is capable of sampling several core specimens with a single biopsy tract. Largevolume cutting needles, ranging from 18 to 14 G, yield enough tissue for most immunochemistry stainings and even for RNA extraction from frozen tissue (Fig. 6.1). Fine-needle aspiration cytology should not be used for diagnosis of Hodgkin lymphoma, but may help in a screening procedure, before biopsy [34]. Several pathologic pitfalls or differential diagnoses should be kept in mind. Drugs such as phenytoin or antibiotics may cause histologic changes within lymph nodes that may mimic Hodgkin lymphoma, particularly the mixed cellularity subtype. Other benign conditions like infectious mononucleosis, lymphoid CD15 hyperplasia, or Castleman disease may produce lymphadenopathy with histologic features similar to those of Hodgkin lymphoma. In fact, the distinction between different diseases, including certain forms of non-Hodgkin lymphoma (NHL), has been made clearer, thanks to a better definition of the entities by the WHO classification. T-cell-rich large B-cell lymphoma is usually included in the differential diagnoses of both nodular lymphocyte-predominant Hodgkin lymphoma and classical Hodgkin lymphoma, while anaplastic CD30-positive NHL may display similar histology to that of classical Hodgkin lymphoma. Nevertheless, molecular studies require adequate material, sometimes including frozen tissue in difficult cases, and the role of the clinician is to make sure that the node to be analyzed is given to an experienced laboratory. If the clinical presentation of disease is not typical for the given pathologic diagnosis, then a review of the pathology by an expert hematopathologist should be considered or even a second biopsy. CD30 Fig. 6.1 Core needle biopsy for Hodgkin lymphoma with immunostainings for CD15 and CD30 6 Clinical Evaluation 6.4 103 taging Systems for Hodgkin S Lymphoma The initial clinical evaluation and staging of patients with Hodgkin lymphoma serve to confirm the Hodgkin lymphoma diagnosis, determine the extent and distribution of disease, evaluate the patient’s fitness for standard treatments, and provide prognostic information (Table 6.1). Several staging systems were developed very early and modified according to the progress made in imaging and treatment of the disease. The Ann Arbor staging was developed in the Table 6.1 Lugano classification Revised staging system for primary nodal lymphomas Stage Involvement I II One node or a group of adjacent nodes Extranodal (E) status Single extranodal lesions Stage I or II Two or more nodal groups on the same side of the diaphragm II bulkya II as above with “bulky” disease Not acceptable Advanced III Nodes on both sides of the diaphragm, nodes Not acceptable above the diaphragm with spleen involvement IV Additional noncontiguous extralymphatic Not acceptable involvement NOTE: Extent of disease is determined by positron emission tomography for avid lymphomas and computed tomography for non-avid histologies. Tonsils, Waldeyer’s ring, and spleen are considered nodal tissue a Whether stage II bulky disease is treated as limited or advanced disease may be determined by histology and a number of prognostic factors Criteria for involvement of site Tissue site Clinical FDG avidity Test Positive finding Lymph nodes Palpable FDG-avid PET-CT Increased FDG histologies CT PET-CT Diffuse uptake Spleen Palpable FDG-avid CT with SUV > histologies liver, solitary Non-avid disease mass, miliary lesions, nodules >13 cm PET-CT Diffuse uptake, Liver Palpable FDG-avid CT mass nodules histologies Non-avid disease Mass lesion(s), CNS Signs, CT leptomeningeal symptoms MRI infiltration, mass CSF assessment lesions, cytology, flow cytometry Other (leg, skin, lung, GI tract, bone, bone Site PET-CTb, Lymphoma marrow) dependent biopsy involvement CSF cerebrospinal fluid, CT computed tomography, FDG fluorodeoxyglucose, MRI magnetic resonance imaging, PET positron emission tomography b PET-CT is adequate for determination of bone marrow involvement and can be considered highly suggestive for involvement of other extralymphatic sites. Biopsy confirmation of those sites can be considered if necessary (continued) 104 J. O. Armitage and J. W. Friedberg Table 6.1 (continued) Revised criteria for response assessment Response and site Complete Lymph nodes and extralymphatic sites Non-measured Organ enlargement New lesions Bone marrow Partial Lymph nodes and extralymphatic sites Non-measured lesions Organ enlargement New lesions Bone marrow No response or stable disease Target nodes/nodal masses, extranodal lesions Non-measured lesions Organ enlargement New lesions Bone marrow Progressive disease Individual target nodes/nodal masses Extranodal lesions PET-CT-based response Complete metabolic response Score 1, 2, or 3c with or without a residual mass on 5PS+ It is recognized that in Waldeyer’s ring or extranodal sites with high physiologic uptake or with activation within the spleen or marrow (e.g., with chemotherapy or myeloid colony-stimulating factors), uptake may be greater than normal in the mediastinum and/or liver. In this circumstance, complete metabolic response may be inferred if uptake at sites of initial involvement is no greater than the surrounding normal tissue even if the tissue has high physiologic uptake Not applicable Not applicable None No evidence of FDG-avid disease in marrow Partial metabolic response Score of 4 or 5+ with reduced uptake compared with baseline and residual mass(es) of any size At interim, these finding suggest responding disease At the end of treatment, these finding indicate residual disease Not applicable Not applicable None Residual uptake is higher than the uptake in normal marrow but reduced compared with baseline (diffuse uptake compatible with reactive changes from chemotherapy allowed). If there are persistent focal changes in the marrow in the context of a nodal response, consideration should be given to further evaluation with MRI or biopsy or an interval scan No metabolic response Score 405 with no significant change in FDG uptake from baseline at interim or end of treatment Not applicable Not applicable None No change from baseline Progressive metabolic disease Score 4 or 5 with an increase in intensity or uptake from baseline New FDG-avid foci consistent with lymphoma at interim or end of treatment assessment 6 Clinical Evaluation 105 Table 6.1 (continued) Non-measured lesions New lesions None New FDG-avid foci consistent with lymphoma rather than another etiology (e.g., leg infection, inflammation). If uncertain regarding etiology of new lesions, biopsy or internal scan may be considered Bone marrow New or recurrent FDG-avid foci 5PS 5-point scale, CT computed tomography, FDG fluorodeoxyglucose, IHC immunohistochemistry, LDi longest transverse diameter of a lesion, MRI magnetic resonance imaging, PET positron emission tomography, PPD cross product of the LDi and perpendicular diameter, SDi shortest axis perpendicular to the LDi, SPD sum of the product of the perpendicular diameters for multiple lesions _A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an interim scan. However, in trials involving PET where de-escalation is investigated, it may be preferable to consider a score of 3 as inadequate response (to avoid undertreatment). Measured dominant lesions: Up to six of the largest dominant nodes, nodal masses, and extranodal lesions selected to be clearly measurable in two diameters. Nodes should preferably be from disparate regions of the body and should include, where applicable, mediastinal and retroperitoneal areas. Non-nodal lesions include those in solid organs (e.g., liver, spleen, kidneys, lungs), GI involvement, cutaneous lesions, or those noted on palpation. Non-measured lesions: Any disease not selected as measured, dominant disease and truly assessable disease should be considered not measured. These sites include any nodes, nodal masses, and extranodal sites not selected as dominant or measurable or that do not meet the requirements for measurability but are still considered abnormal, as well as truly assessable disease, which is any site of suspected disease that would be difficult to follow quantitatively with measurement, including pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot be confirmed and followed by imaging. In Waldeyer’s ring or in extranodal sites (e.g., GI tract, liver, bone marrow), FDG uptake may be greater than in the mediastinum with complete metabolic response, but should be no higher than the surrounding normal physiologic uptake (e.g., with marrow activation as a result of chemotherapy or myeloid growth factors) c PET 5PS: 1, no uptake above background; 2, uptake _ mediastinum; 3, uptake _ mediastinum but _ liver; 4, uptake moderately _ liver; 5, uptake markedly higher than the liver and/or new lesions; X, new areas of uptake unlikely to be related to lymphoma JCO 2014 [37] 1970s, when radiotherapy was the main curative treatment option, and was based on the tendency of Hodgkin lymphoma to spread to contiguous lymph nodes [35]. Since the Ann Arbor staging, several significant changes in the management of Hodgkin lymphoma have taken place. The Cotswolds modification of the Ann Arbor staging system was introduced in 1989 to approve the use of CT scanning for the detection of intra-abdominal disease, to formalize a definition of disease bulk, and to provide guidelines for evaluating the response to treatment [36]. The current standard is the Lugano classification which addresses both staging and re-staging (Table 6.1) [37]. A prognostic factor score for advanced Hodgkin lymphoma treated by chemotherapy has been worked out, based mostly on biological parameters, including serum albumin <4 g/dL, hemoglobin <10.5 g/dL, male sex, stage IV disease, age >45 year, white cell count >15,000 mm−3, and lymphocyte count <600 mm−3 [38]. These prognostic factors are used to define risk-adapted therapy. However, as combined modality treatment with modern chemotherapy has become the standard procedure for patients with early-stage disease, the risk of relapse is reduced, and some of these factors are no longer associated with a high risk of relapse. In addition, computed tomography (CT) and fluorine-18- deoxyglucose positron emission tomography (FDG-PET) are now routinely used for the staging and evaluation of the response to treatment. PET-CT provides reliable information on treatment efficacy. J. O. Armitage and J. W. Friedberg 106 6.5 Imaging Evaluation of the Extent of Disease and early-stage extranodal disease. Thus, even experienced oncologists vary in their stage assignment of patients with nearby but disconThanks to the progress and availability of imag- tinuous extranodal involvement [43]. However, ing techniques, it has been possible to improve the involvement of two or more noncontiguous the accuracy of clinical staging, so that invasive extranodal sites should typically be considered pathologic procedures are rarely necessary. At indicative of stage IV disease. The use of risk- present, the established radiological technique adapted treatment with chemotherapy has for the diagnosis of Hodgkin lymphoma is FDG- reduced the importance of such factors. The definition of bulk has varied considerPET [39]. FDG-PET is based on the increased glycolysis ably in the literature. For the mediastinum, one of cancer cells. This is visualized using the radio- definition involved measuring the greatest active glucose analog FDG, which after phos- transverse diameter of the mediastinal mass on phorylation is metabolically trapped within the a standard posteroanterior chest radiograph and cell. Thus, FDG-PET has become an established dividing it by the maximal diameter of the chest imaging modality to stage, restage, and monitor wall at its pleural surfaces, usually at the level therapy and detect recurrent lymphoma. PET and of the diaphragm or alternatively at the T5–T6 CT, which, respectively, supply metabolic and interspace (Cotswolds approach) [36]. A ratio anatomic information, are complementary, and exceeding one third (1:3) was considered bulky interpretation of the PET portion of the study is and a negative feature among patients treated more accurate when the results of PET correlate with RT alone or chemotherapy alone. There with those of CT [40, 41]. Therefore, integrated are no widely accepted criteria for the definiPET-CT systems were developed which are now tion of bulk using measurements obtained from the standard care [42]. If PET-CT is not available, CT scans: the Cotswolds Committee recoman alternative imaging technique is computed mended that to constitute bulk, a nodal mass tomography (CT) scan of the neck, chest, abdo- must be greater than 10 cm in diameter [36], men, and pelvis. In rare cases where it is desir- whereas in some ongoing trials, bulk was able to avoid radiation exposure (such as defined as confluent nodal masses greater than pregnancy), MRI may be utilized as a substitute 7 cm [44]. The Lugano criteria states that a single nodal mass, in contrast to multiple smaller for CT imaging. It is important that imaging results be inter- nodes, of 10 cm or greater than a third of the preted within the framework of the known pat- transthoracic diameter at any level of thoracic terns of spread and other prognostic factors. A vertebrae as determined by CT is the definition certain degree of variation in the size of medias- of bulky disease for HL. A chest X-ray is not tinal and hilar nodes is normal, but those measur- required to determine bulk because of its high ing more than 10 mm on the shortest cross section concordance with CT [37]. It appears that FDG-PET can largely eliminate can be considered abnormal. However, although the necessity for doing bone marrow biopsies in clearly abnormal findings on CT scanning may patients with Hodgkin lymphoma. One report of be indicative of Hodgkin lymphoma, there is a 454 patients found that no patients with a FDG- risk of false positives, particularly in the abdomen, when interpreting these findings. Therefore, PET scan assigned stage of 1 or 2 had a positive when lymph nodes in the 15–20 mm range are bone marrow biopsy. The presence of focal skelseen, uptake on FDG-PET-CT is indicative of etal FDG-PET scan lesions identified positive and negative bone marrow biopsies with a sensiinvolvement by lymphoma. Substantial variations in stage assignment tivity and specificity of 85% and 86%. A negative have nevertheless been demonstrated among FDG-PET scan for skeletal lesions had a 99% patients with extranodal involvement, specifi- negative predictive value for the results of a bone cally regarding the distinction between stage IV marrow biopsy [37, 45]. 6 Clinical Evaluation 6.6 linical Evaluation During C Therapy Clinical evaluation during treatment can be an important component of the individualization of treatment intensity. A rapid early response to initial therapy is increasingly recognized as a favorable prognostic factor among Hodgkin lymphoma patients. Response can be evaluated by FDG- PET-CT after two or three cycles of chemotherapy. Performing PET early during treatment has also proved to be prognostically important and has been incorporated into the response criteria. Thus, a meta-analysis demonstrated that for lowto intermediate-risk Hodgkin lymphoma patients, PET may be a good prognostic indicator after a few cycles of standard chemotherapy [46]. FDG-PET scans performed after two cycles of therapy are increasingly being utilized to guide subsequent treatment [47–50]. The results of interim FDG-PET scans have been used to shorten the duration of therapy, to complete a “standard” course of chemotherapy, to escalate treatment to more intensive chemotherapy in patients with a slow response, and to deescalate therapy in patients with an excellent response. 6.7 Definition of the Response to Treatment FDG-PET scans have revolutionized determination of response to therapy in patients with Hodgkin lymphoma. The often called “Lugano criteria” have become the standard approach in determining treatment response [51]. A key to improving our ability to determine response to therapy was standardization of interpretation of PET scans. The so-called 5-point or Deauville scoring system is recommended in the Lugano criteria (Table 6.2) [37]. This system appears to have a high interobserver agreement. There has been debate about what should be the definition of a complete remission using the 5-point score. The consensus appears to be a 5-point score of 3 or less is the definition of a complete remission at the end of therapy. Some studies of interim PET scans, 107 Table 6.2 5-point score (Deauville score) Score 1 2 3 4 5 Definition No uptake in sites of suspected lymphoma Uptake but less than that seen in the mediastinum Uptake greater than seen in the mediastinum, but less than seen in the liver Uptake moderately higher than seen in the liver Uptake markedly higher than the liver and/or new lesions where the interim PET scan will be used to guide possible treatment changes, have chosen to use a more conservative 5-point score of 2 or less to identify an early complete remission [47]. Ongoing studies are evaluating other criteria, such as total metabolic tumor volume change, and SUV change over time which may have less variability between observers. 6.8 Complete Remission The patient has no clinical, radiologic, or other evidence of Hodgkin lymphoma. Changes due to the effects of previous therapy (i.e., radiation fibrosis) may, however, be present. The category (CRu) has been eliminated from the updated response criteria and now denotes patients whose remission status is unclear, because they display no clinical evidence of Hodgkin lymphoma, but some radiologic abnormality that persists at a site of previous disease. In this respect, it is generally recognized that imaging abnormalities may persist following treatment and do not necessarily signify active disease [52]. It must be borne in mind that after mediastinal RT, thymic rebound, reactive lymph node hyperplasia, or subclinical radiation pneumonitis may lead to abnormalities on FDG-PET [53]. To avoid false-positive interpretations, some authors recommend that FDG-PET re-evaluation should be delayed until 3 months after the completion of mediastinal RT, although the characteristic appearance of post-RT lung changes occurring before 3 months can usually be distinguished from lymphoma by experienced nuclear radiographers [42]. J. O. Armitage and J. W. Friedberg 108 The inclusion of PET in the new response criteria and the removal of CRu have simplified the management of lymphoma patients by removing some of the limiting factors of CT, which include the size of lymph nodes that indicates involvement, the differentiation of unopacified bowel from lesions in the abdomen and pelvis, the inability to distinguish viable tumor from necrotic/fibrotic lesions after therapy, and the characterization of small lesions. A combined PET-CT scan with a Deauville score of 1, 2, or 3 is consistent with complete remission. 6.9 Follow-Up Management The manner in which patients are evaluated after completing treatment may vary according to whether treatment was administered in a clinical trial or clinical practice and whether it was delivered with curative of palliative intent. In a clinical trial, the requirement of uniform reassessment may lead to follow-up studies that would not be routinely done in practice. Follow-up should involve identifying relapse but also focus on identifying and dealing with long-term adverse effects of treatment. These can include secondary cancers, cardiac toxicity, thyroid disease, depression, and fertility issues [54]. Good clinical judgment, careful recording of history, and a thorough physical examination are the most important components of monitoring patients after treatment. A complete blood count, selected serum chemistry studies, and a sedimentation rate are frequently done with each visit. However, there is no evidence to support the need for regular surveillance CT scans. The patient or physician identifies the relapse in more than 80% of cases without imaging studies [55]. The most important potential reason to do surveillance imaging would be the detection of early relapse that allowed early institution of salvage therapy and increased survival. However, there is no evidence to support this hypothesis. One study of 241 patients that compared patients treated at different centers who did or did not do routine surveillance imaging found a 97% overall survival rate in patients who received routine surveillance imaging and a 96% 5-year survival rate in patients who were only followed clinically [56]. In both groups, salvage therapy was effective with only one patient in the routine surveillance imaging group dying of Hodgkin lymphoma. It was calculated that each relapse detected by surveillance imaging costs $629,615, with no benefit in eventual outcome. Similar results have been found in the use of surveillance imaging in pediatric Hodgkin lymphoma [57]. In addition to financial costs, surveillance imaging has other “side effects.” One study found that patients undergoing surveillance imaging had increased anxiety and fear associated with the images [58]. In addition, it is known that CT scans deliver a high level of radiation and are a significant cause of cancer [59, 60]. An alternative to using CT scans would be the use of FDG-PET scans as a potential tool for the detection of relapse. However, in a prospective study of 36 Hodgkin lymphoma patients, routine FDG-PET correctly identified all 5 relapses that followed treatment, but had a falsepositive rate of 55% [61]. A more recent study using PET-CT scans showed a positive predictive value of only 28% for routine PET-CT scans for surveillance for relapse [62]. Given the observation that patients with cHL who are event-free at 2 years have an excellent outcome regardless of baseline prognostic factors, surveillance imaging beyond 2 years has not been demonstrated to have value [63]. 6.10 Conclusion The careful and accurate clinical evaluation of patients with Hodgkin lymphoma from presentation to follow-up in remission has a significant impact on treatment outcome. The ability to perform an excellent history and physical and knowledge regarding when, where, and how to perform laboratory evaluations, images, and biopsies are necessary for excellent care. References 1. Gerstner ER, Abrey LE, Schiff D, Ferreri AJ, Lister A, Montoto S et al (2008) CNS Hodgkin lymphoma. Blood 112(5):1658–1661 6 Clinical Evaluation 2. Tassies D, Sierra J, Montserrat E, Marti R, Estrach T, Rozman C (1992) Specific cutaneous involvement in Hodgkin’s disease. Hematol Oncol 10(2):75–79 3. Granger W, Whitaker R (1967) Hodgkin’s disease in bone, with special reference to periosteal reaction. Br J Radiol 40(480):939–948 4. Pel PK (1887) Pseudoleukämie oder chronisches Rückfallsfieber? Symptomatol Sogenannten Pseudoleukämie II:644 5. Ebstein W (1887) Das chronische Rückfallsfieber, eine neue Infectionskrankheit. Berl Klin Wochenschr 24:565 6. Chang JC, Gross HM (1985) Neoplastic fever responds to the treatment of an adequate dose of naproxen. J Clin Oncol 3(4):552–558 7. Bichel J (1959) The alcohol-intolerance syndrome in Hodgkin’s disease. Acta Med Scand 164(2):105–112 8. James AH (1960) Hodgkin’s disease with and without alcohol-induced pain. A clinical and histological comparison. Q J Med 29:47–66 9. Simon S, Azevedo SJ, Byrnes JJ (1985) Erythema nodosum heralding recurrent Hodgkin’s disease. Cancer 56(6):1470–1472 10. Ronchese F, Gates DC (1956) Ichthyosiform atrophy of the skin in Hodgkin’s disease. N Engl J Med 255(6):287–289 11. Lucker GP, Steijlen PM (1995) Acrokeratosis paraneoplastica (Bazex syndrome) occurring with acquired ichthyosis in Hodgkin’s disease. Br J Dermatol 133(2):322–325 12. Noto G, Pravata G, Miceli S, Arico M (1994) Granulomatous slack skin: report of a case associated with Hodgkin’s disease and a review of the literature. Br J Dermatol 131(2):275–279 13. Milionis HJ, Elisaf MS (1998) Psoriasiform lesions as paraneoplastic manifestation in Hodgkin’s disease. Ann Oncol 9(4):449–452 14. Dabbs DJ, Striker LM, Mignon F, Striker G (1986) Glomerular lesions in lymphomas and leukemias. Am J Med 80(1):63–70 15. Rieke JW, Donaldson SS, Horning SJ (1989) Hypercalcemia and vitamin D metabolism in Hodgkin’s disease. Is there an underlying immunoregulatory relationship? Cancer 63(9):1700–1707 16. Seymour JF, Gagel RF (1993) Calcitriol: the major humoral mediator of hypercalcemia in Hodgkin’s disease and non-Hodgkin’s lymphomas. Blood 82(5):1383–1394 17. Laforga JB, Vierna J, Aranda FI (1994) Hypercalcaemia in Hodgkin’s disease related to prostaglandin synthesis. J Clin Pathol 47(6):567–568 18. Lieberman DA (1986) Intrahepatic cholestasis due to Hodgkin’s disease. An elusive diagnosis. J Clin Gastroenterol 8(3 Pt 1):304–307 19. Hubscher SG, Lumley MA, Elias E (1993) Vanishing bile duct syndrome: a possible mechanism for intrahepatic cholestasis in Hodgkin’s lymphoma. Hepatology 17(1):70–77 20. Hammack J, Kotanides H, Rosenblum MK, Posner JB (1992) Paraneoplastic cerebellar degeneration. 109 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. II. Clinical and immunologic findings in 21 patients with Hodgkin’s disease. Neurology 42(10):1938–1943 Reid TJ III, Mullaney M, Burrell LM, Redmond J III, Mangan KF (1994) Pure red cell aplasia after chemotherapy for Hodgkin’s lymphoma: in vitro evidence for T cell mediated suppression of erythropoiesis and response to sequential cyclosporin and erythropoietin. Am J Hematol 46(1):48–53 Samoszuk M, Nansen L (1990) Detection of interleukin- 5 messenger RNA in reed-Sternberg cells of Hodgkin’s disease with eosinophilia. Blood 75(1):13–16 Di Biagio E, Sanchez-Borges M, Desenne JJ, Suarez-Chacon R, Somoza R, Acquatella G (1996) Eosinophilia in Hodgkin’s disease: a role for interleukin 5. Int Arch Allergy Immunol 110(3):244–251 Bjorkholm M, Holm G, Merk K (1982) Cyclic autoimmune hemolytic anemia as a presenting manifestation of splenic Hodgkin’s disease. Cancer 49(8):1702–1704 Kirshner JJ, Zamkoff KW, Gottlieb AJ (1980) Idiopathic thrombocytopenic purpura and Hodgkin’s disease: report of two cases and a review of the literature. Am J Med Sci 280(1):21–28 Heyman MR, Walsh TJ (1987) Autoimmune neutropenia and Hodgkin’s disease. Cancer 59(11):1903–1905 Kojima H, Takei N, Mukai Y, Hasegawa Y, Suzukawa K, Nagata M et al (2003) Hemophagocytic syndrome as the primary clinical symptom of Hodgkin’s disease. Ann Hematol 82(1):53–56 Slease RB, Schumacher HR (1977) Deficiency of coagulation factors VII and XII in a patient with Hodgkin’s disease. Arch Intern Med 137(11):1633–1635 Shoho AR, Go RS, Tefferi A (2000) 22-Year-old woman with severe microcytic anemia. Mayo Clin Proc 75(8):861–864 De Kerviler E, Gossot D, Frija J (1996) Localization techniques for the thoracoscopic resection of pulmonary nodules. Int Surg 81(3):241–244 de Kerviler E, Guermazi A, Zagdanski AM, Meignin V, Gossot D, Oksenhendler E et al (2000) Image- guided core-needle biopsy in patients with suspected or recurrent lymphomas. Cancer 89(3):647–652 Picardi M, Gennarelli N, Ciancia R, De Renzo A, Gargiulo G, Ciancia G et al (2004) Randomized comparison of power Doppler ultrasound-directed excisional biopsy with standard excisional biopsy for the characterization of lymphadenopathies in patients with suspected lymphoma. J Clin Oncol 22(18):3733–3740 Agid R, Sklair-Levy M, Bloom AI, Lieberman S, Polliack A, Ben-Yehuda D et al (2003) CT-guided biopsy with cutting-edge needle for the diagnosis of malignant lymphoma: experience of 267 biopsies. Clin Radiol 58(2):143–147 Landgren O, Porwit MacDonald A, Tani E, Czader M, Grimfors G, Skoog L et al (2004) A prospective comparison of fine-needle aspiration cytology and histopathology in the diagnosis and classification of lymphomas. Hematol J 5(1):69–76 110 35. Rosenberg SA, Boiron M, DeVita VT Jr, Johnson RE, Lee BJ, Ultmann JE et al (1971) Report of the committee on Hodgkin’s disease staging procedures. Cancer Res 31(11):1862–1863 36. Lister TA, Crowther D, Sutcliffe SB, Glatstein E, Canellos GP, Young RC et al (1989) Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin’s disease: Cotswolds meeting. J Clin Oncol 7(11):1630–1636 37. Cheson BD, Fisher RI, Barrington SF, Cavaoli F, Schwarz LH, Zucca E, Lister TA (2014) Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 32(27):3059–3067 38. Hasenclever D, Diehl V (1998) A prognostic score for advanced Hodgkin’s disease. International prognostic factors project on advanced Hodgkin’s disease. N Engl J Med 339(21):1506–1514 39. Armitage JO (2005) Staging non-Hodgkin lymphoma. CA Cancer J Clin 55(6):368–376 40. Blodgett TM, Meltzer CC, Townsend DW (2007) PET/ CT: form and function. Radiology 242(2):360–385 41. von Schulthess GK, Steinert HC, Hany TF (2006) Integrated PET/CT: current applications and future directions. Radiology 238(2):405–422 42. Kazama T, Faria SC, Varavithya V, Phongkitkarun S, Ito H, Macapinlac HA (2005) FDG PET in the evaluation of treatment for lymphoma: clinical usefulness and pitfalls. Radiographics 25(1):191–207 43. Connors JM, Klimo P (1984) Is it an E lesion or stage IV? An unsettled issue in Hodgkin’s disease staging. J Clin Oncol 2(12):1421–1423 44. Laskar S, Gupta T, Vimal S, Muckaden MA, Saikia TK, Pai SK et al (2004) Consolidation radiation after complete remission in Hodgkin’s disease following six cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapy: is there a need? J Clin Oncol 22(1):62–68 45. El-Galaly TC, d’Amore F, Mylam KJ et al (2012) Routine bone marrow biopsy has little or no therapeutic consequence for positron emission tomography/computed tomography-staged treatment-naïve patients with Hodgkin lymphoma. J Clin Oncol 30(36):4508–4514 46. Terasawa T, Lau J, Bardet S, Couturier O, Hotta T, Hutchings M et al (2009) Fluorine-18- fluorodeoxyglucose positron emission tomography for interim response assessment of advanced-stage Hodgkin’s lymphoma and diffuse large B-cell lymphoma: a systematic review. J Clin Oncol 27(11):1906–1914 47. Radford J, Illidge T, Counsell N, Hancock B, Pettengell R, Johnson P, Wimperis J, Culligan D, Popova B, Smith P, McMillan A, Brownell A, Kruger A, Lister A, Hoskin P, O’Doherty M, Barrington S (2015) Results of a trial of PET-directed therapy for early-stage Hodgkin’s lymphoma. N Engl J M 372(17):1598–1607 J. O. Armitage and J. W. Friedberg 48. Raemaekers JMM, Andre MPE, Federico M, Girinsky T, Oumedaly R, Brusamolino E, Brice P, Ferme C, van der Maazen R, Gotti M, Bouabdallah R, Sebban CJ, Lievens Y, Re A, Stamatoullas A, Morschhauser F, Lugtenburg PJ, Abruzzese E, Olivier P, Casasnovas RO, van Imhoff G, Raveloarivahy T, Bellei M, vad der Borght T, Bardet S, Versari A, Hutchings M, Meignan M, Fortpied C (2014) Omitting radiotherapy in early positron emission tomography-negative stage I/II Hodgkin lymphoma is associated with an increased risk of early relapse: clinical results of the preplanned interim analysis of the randomized DORTC/LYSA/ FIL H10 trial. J Clin Oncol 32(12):1188–1194 49. Press OW, Li H, Schoder H, Straus DJ, Moskowitz CH, LeBlanc M, Rimsza LM, Bartlett NL, Evens AM, Mittra ES, LaCasce AN, Sweetenham JW, Barr PM, Fanale MA, Knopp MC, Noy A, Hsi ED, Cook JR, Lechowicz MJ, Gascoyne RD, Leonard JP, Kahl BS, Cheson BD, Fisher RI, Friedbert JW (2016) US intergroup trial of response-adapted therapy for stage III to IV Hodgkin lymphoma using early interim fluorodeoxyglucose- positron emission tomography imaging: southwest oncology group S0816. J Clin Oncol 34(17):2020–2027 50. Johnson P, Federico M, Kirkwood A, Fossa A, Berkahn L, Carella A, d’Amore F, Englad G, Franceschetto A, Fulham M, Luminari S, O’Doherty M, Patrick P, Roberts T, Sidra G, Stevens L, Smith P, Trotman J, Viney Z, Radford J, Barrington S (2016) Adapted treatment guided by interim PET-CT in advanced Hodgkin’s lymphoma. N Engl J Med 374(25):2419–2429 51. Barrington SF, Mikhaeel NG, Kostakoglu L, Meignan M, Hutchings M, Mueller SP, Schwartz LH, Zucca EM, Fisher RI, Trotman J, Hoekstra OS, Hicks RJ, O’Doherty MJ, Hustinx R, Biggi A, Cheson BD (2014) Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group. J Clin Oncol 32(27):3048–3058 52. Radford JA, Cowan RA, Flanagan M, Dunn G, Crowther D, Johnson RJ et al (1988) The significance of residual mediastinal abnormality on the chest radiograph following treatment for Hodgkin’s disease. J Clin Oncol 6(6):940–946 53. Jerusalem G, Hustinx R, Beguin Y, Fillet G (2005) Positron emission tomography imaging for lymphoma. Curr Opin Oncol 17(5):441–445 54. Ng AK (2014) Current survivorship recommendations for patients with Hodgkin lymphoma: focus on late effects. Blood 124(23):3373–3379 55. Henry-Amar M, Friedman S, Hayat M, Somers R, Meerwaldt JH, Carde P et al (1991) The EORTC lymphoma cooperative group. Erythrocyte sedimentation rate predicts early relapse and survival in early-stage Hodgkin disease. Ann Intern Med 114(5):361–365 56. Pingali SR, Jewell SW, Havlat L et al (2014) Limited utility of routine surveillance imaging for classical 6 57. 58. 59. 60. Clinical Evaluation Hodgkin lymphoma patients in first complete remission. Cancer 120:2122 Voss SD, Chen L, Constine LS et al (2012) Surveillance computed tomography imaging and detection of replace in intermediate – and advancedstage pediatric Hodgkin’s lymphoma: a report from the Children’s oncology group. J Clin Oncol 30(21):2635–2640 Thompson CA, Charlson ME, Schenkein E et al (2010) Surveillance CT scans are a source of anxiety and fear of recurrence in long-term lymphoma survivors. Ann Oncol 21(11):2262–2266 Berrington de Gonzalez A, Mahesh M, Kim KP et al (2009) Projected cancer risks from computed tomographic scans performed in the United States in 2007. Arch Intern Med 169(22):2071–2077 Smith-Bindman R, Lipson J, Marcus R et al (2009) Radiation dose associated with common computed tomography examinations and the associated life- 111 time attributable risk of cancer. Arch Intern Med 169(22):2078–2086 61. Jerusalem G, Beguin Y, Fassotte MF et al (2003) Early detection of relapse by whole-body positron emission tomography in the follow-up of patients with Hodgkin’s disease. Ann Oncol 14(1):123–130 62. El-Galay TC, Mylam KJ, Brown P et al (2012) Positron emission tomography/computed tomography surveillance in patients with Hodgkin lymphoma in first remission has a low positive predictive value and high costs. Haematologica 97(6):931–936 63. Hapgood G, Zheng Y, Sehn LH, Villa D, Klasa R, Gerrie AS, Shenkier T, Scott DW, Gascoyne RD, Slack GW, Parsons C, Morris J, Pickles T, Connors JM, Savage KJ (2016) Evaluation of the risk of relapse in classical Hodgkin lymphoma at event-free survival time points and survival comparison with the general population in British Columbia. J Clin Oncol 34(21):2493–2500 7 Functional Imaging in Hodgkin Lymphoma Andrea Gallamini, Bruce Cheson, and Martin Hutchings Contents 7.1 Introduction 114 7.2 History of Imaging in Hodgkin Lymphoma 115 7.3 7.3.1 7.3.2 Background of PET and the FDG Tracer asic Principles of PET B The FDG Tracerc 115 115 116 7.4 7.4.1 7.4.2 7.4.3 7.4.4 7.4.4.1 7.4.4.2 7.4.5 7.4.6 7.4.7 7.4.8 PET in Clinical Management of Hodgkin Lymphoma taging S Early Assessment of Chemosensitivity Final Response Assessment Interpretation Criteria Interim PET Scan End-of-Treatment PET Scan Treatment Response Assessment to Immune Checkpoint Inhibitors PET in Radiotherapy Planning PET for Response Prediction During Salvage Treatment PET for Follow-Up of HL Patients in Complete Remission 116 116 118 119 121 121 121 122 122 125 126 7.5 7.5.1 7.5.2 7.5.3 7.5.4 PET Response-Adapted Therapy arly-Stage HL E Advanced-Stage HL Post-chemotherapy PET/CT-Driven Consolidation Radiotherapy PET/CT-Adapted Therapy in Relapsed HL 127 127 128 129 129 7.6 7.6.1 7.6.1.1 7.6.1.2 7.6.1.3 7.6.2 7.6.3 Toward Revised Criteria for PET Scan Interpretation ualitative vs. Semiquantitative Assessment Q From Anatomical to Functional Imaging Toward New Criteria for Response Assessment of New Drugs Biomarker Integration in Response Criteria Interim PET End-of-Treatment PET 130 130 130 131 131 131 132 A. Gallamini (*) · B. Cheson · M. Hutchings Department of research and Clinical innovation, Antoine Lacassagne Cancer Center, Nice, France e-mail: andrea.GALLAMINI@nice.unicancer.fr © Springer Nature Switzerland AG 2020 A. Engert, A. Younes (eds.), Hodgkin Lymphoma, Hematologic Malignancies, https://doi.org/10.1007/978-3-030-32482-7_7 113 A. Gallamini et al. 114 7.7 FDG-PET/MRI 132 7.8 7.8.1 7.8.2 7.8.2.1 7.8.2.2 Future Perspectives ther Tracers O Quantitative Methods for PET Reading (SUV, MTV, TLG) Semiquantitative Assessment Metabolic Tumor Volume 133 133 134 134 134 7.9 General Recommendations for the Use of PET in HL 135 References 7.1 Introduction Hodgkin lymphoma (HL) has become a highly curable malignancy with more than 90% of patients alive and 80% considered cured after long-term follow-up [1, 2]. Risk-adapted strategies have further led to improved outcomes for high-risk patients, with less toxicity for low-risk patients [3–7]. The staging of HL has undergone a major evolution. Imaging technology in this disease has evolved over the past decades from the lymphangiogram to the intravenous pyelogram, ultrasound, liver-spleen radionuclide scan, computed tomography (CT), and magnetic resonance imaging. Gallium scanning required a 2-day interval between injection and scanning, which was not clinically practical [8]. Today, positron emission tomography combined with computed tomography (PET-CT) is the basis for staging and response assessment [9–12]. Response assessment with CT uses changes in tumor size as the main criterion. However, tumor shrinkage occurs over time, and fibrosis in HL may take years following treatment to disappear. With these limitations, CT does not provide a sufficiently accurate early assessment of response [13]. In contrast, PET depends on tumor metabolism rather than anatomy. Positron emission tomography using [18F]-fluoro-2-deoxy-d-glucose (FDG-PET) provides an assessment of chemosensitivity when performed early during standard treatment [14–17]. In HL tissue, scattered neoplastic Hodgkin Reed-Sternberg cells usually account for less than 1% of the total cell count. Recently it has been recognized that the malignant cells are able 135 to evade the immune system because of overproduction of the programmed death ligands (PDL) PDL-1 and PDL-2 [18], despite the extensive infiltration of lymph nodes by inflammatory cells. The consequence is suppression of T-cell activation and failure of immune recognition. The relevance of this interaction is exemplified by the efficacy of checkpoint inhibitors in HL patients [19–21]. Functional imaging is critical for accurate staging, restaging, and follow-up assessment of patients with HL [9, 10]. Metabolic imaging is currently performed using FDG-PET. This technology has become the most sensitive and specific technology, allowing us to better manage HL patients [10]. A variety of clinical studies have established the role of PET-CT scanning in the risk-adapted management of HL patients, leading to improved outcomes and reduced toxicity [3, 4, 22]. Despite major advances in patient outcome, further refinements are warranted not only in the interpretation of PET-CT but also in determining how best to incorporate PET into patient management. In this chapter, we will review the history of metabolic imaging in HL and its usefulness in the staging and response assessment, including its role in risk-adapted strategies allowing for improved outcome for high-risk patients and decreased toxicity for low-risk patients. We will also discuss the current gaps in the application of PET-CT, potential means to improve the current response criteria, and speculate on the future of metabolic imaging in the management of HL patients. Newer and potentially more specific PET tracers are also under investigation and will be discussed in this chapter. 7 Functional Imaging in Hodgkin Lymphoma 7.2 History of Imaging in Hodgkin Lymphoma HL has been for long considered the paradigm for tumor staging in oncology [23]. In the early 1970s, the Ann Arbor conference [23] and later the Cotswold revised classification [24] introduced the concept that the disease spread per se is able to identify distinct categories of patients with different prognosis and treatment outcome. Staging laparotomy using splenectomy and multiple nodal and organ biopsies including bone marrow trephine biopsy (BMB) was originally proposed as an accurate diagnostic means for tumor staging [25]. This procedure had the merit of shedding more light on the physiopathology of tumor spread, becoming the “gold standard” to assess sensitivity, specificity, and overall accuracy of newly emerging radiological imaging [26]. In April 1970, during the Ann Arbor conference in Michigan, the concept of four-stage clinical staging (CS) was initially introduced to distinguish patients staged with clinical and radiological means from those more accurately staged with pathological staging (PS) [23]. Nonetheless, the high accuracy of surgical staging was deemed no longer necessary with the advent of active multi-agent chemotherapy such as MOPP (mechlorethamine, vincristine, procarbazine, and prednisone). However, MOPP also led to sterilization in more than 80% of patients treated [27]. Bipedal lymphography and contrast-enhanced computed tomography (ceCT) very soon superseded the invasive procedures of PS including staging laparotomy, with the notable exception of BMB. The latter became the only invasive technique used for staging, as CT proved insufficient for evaluation of HL infiltration in the bone marrow. Meanwhile, the disease burden and the host reaction against the tumor proved as the main prognostic parameters correlating with survival. This subsequently provided the basis for a new classification of prognostic factors in HL as (a) tumor related, (b) host related, and (c) environment related [28], providing the frame for three different risk groups of HL patients with different long-term prognosis: the early favorable, early unfavorable, and advanced HL [29]. 115 The clinical and radiological procedures of HL staging, the definition of bulky nodal lesion, and the nomenclature to define response to treatment have been described and standardized during the Cotswold meeting in 1989 [24]. In the early nineties, another step forward in the tumor staging accuracy was the use of functional imaging with 67Ga scintigraphy initially, and later with positron emission tomography (PET), using the glucose analogue 18F-fluorodeoxyglucose (FDG). The latter was able to trace viable tumor tissue selectively, thus resulting in the more accurate diagnostic tool so far evaluable for lymphoma staging and restaging. With the introduction of integrated FDG-PET/CT scanners, unsuspected nodal and extranodal lesions were detected, which otherwise would have been missed by the current diagnostic tools, including ceCT and BMB [30]. FDG-PET/CT showed a better sensitivity and a similar specificity compared to FDG- PET stand alone and CeCT in detecting nodal and extranodal disease [9, 10]. In HL and diffuse large B-cell lymphoma (DLBCL), the bone and bone marrow was by far the most frequently detected extranodal site followed by the liver, lung, and spleen. Due to the lower overall accuracy of BMB compared to FDG-PET/CT in detecting bone or bone marrow, BMB was abandoned as the standard diagnostic tool to detect BMI by HL and DLBCL [31, 32]. 7.3 Background of PET and the FDG Tracer 7.3.1 Basic Principles of PET PET is a functional imaging modality based on measurements of radiation from the decay of positron-emitting radioactive nuclides. These nuclides have excess protons which transform to neutrons under the emission of positrons (β+-decay). The positron randomly travels 2–3 mm in the tissue before it annihilates via collision with an electron, and thereby emitting two photons (each 511 keV) at an angle very close to 180°. The two photons are registered by the ring of scintillation detectors in the PET scanner. Two A. Gallamini et al. 116 511 keV photons registered simultaneously (or within a very narrow time frame) by two opposing detectors are considered a coincidence event originating from positron annihilation. A PET scanner holds several thousands of scintillation detectors, organized in detector rings. The detector rings may be separated by leaded ring collimators (2D mode) in order to limit sources of noise in the PET images. Data acquisition can be either static or dynamic, and the data generated provide both quantitative information and images. The spatial resolution of PET is typically around 3–5 mm, limited by the number of detectors and by the random travel of the positron [33]. The unstable positron-emitting isotopes used in PET are produced by fusion of stable nuclei with other particles. This is possible in a cyclotron, in which the electrical repulsion between particles is overcome by accelerating particles up to 30% of the speed of light with a beam toward the target [34]. A radiochemistry laboratory is needed to attach the isotopes to relevant tracer molecules. The most common PET isotope molecules are 15 O, 13N, 11C, and 18F [35]. PET tracers of relevance to oncology target glucose metabolism, hypoxia, blood flow, proliferation, amino acid transport, protein synthesis, DNA synthesis, apoptosis, and specific receptors. Fusion PET/CT scanners incorporate the hardware of high-resolution CT and PET into one scanner, so that PET and CT as well as fusion images are obtained in one scanning session. PET/CT scanners have been available commercially since the late 1990s and have now replaced the single-modality PET scanners. PET/CT provide anatomical localization of the FDG uptake, as well as better distinction between pathological findings and normal physiological uptake [36]. porter molecules (GLUT 1–5), which are overexpressed in cancer cells [38–40]. In the cell, FDG is phosphorylated by hexokinase to FDG-6phosphate, which does not cross the cell membrane. Due to the low levels of glucose-6- phosphatase in cancer cells and the inability of FDG-6-phosphate to enter glycolysis, the tracer is retained in the cancer cells [41]. Generally, the uptake of FDG is related to the number of viable tumor cells [42, 43], but is dependent also on a number of physiological factors including regional blood flow, blood glucose level, and tissue oxygenation [44, 45]. FDG uptake is very high in HL, but since the HRS cells only make up a small fraction of the tumor volume, the surrounding cells are accountable for most of the increased FDG metabolism. FDG uptake is not tumor specific and accumulates in a range of nonmalignant tissues, such as the brain, heart, and kidneys. Furthermore, activated inflammatory cells take up FDG, which can cause false-positive results in cancer imaging studies [46, 47]. This is obviously important not only since HL patients frequently experience infections but also because chemotherapy and radiotherapy induce inflammatory responses in the tumor cells and the surrounding tissue. Increased tracer uptake is seen in response to the early-phase tissue inflammation induced by chemotherapy, while a “stunned” uptake is observed immediately after therapy [48, 49]. 7.4 ET in Clinical Management P of Hodgkin Lymphoma 7.4.1 Staging Currently, the original Ann Arbor nomenclature for HL staging is the standard tool to define disease prognosis and to guide treatment [23]. In 7.3.2 The FDG Tracer the recent consensus statement of Lugano in 2014 for the use of FDG-PET for HL staging, The glucose analogue 2-[18F]fluoro-2- the presence or absence of Systemic symproms deoxyglucose (FDG) is the most versatile and the (A or B substage definition) was still considered most widely used PET tracer. FDG is administered useful in HL to guide treatment as “B sympby intravenous injection. The use of FDG in tumor toms” were still considered adverse prognostic imaging is based on Warburg’s finding that cancer indicators [9]. cells show accelerated glucose metabolism [37]. As previously mentioned, a committee of FDG is transported into the cell via glucose trans- experts convened in 2014 so that FDG-PET/CT 7 Functional Imaging in Hodgkin Lymphoma became the standard method to stage and restage the vast majority of lymphomas, including HL [9, 10]. FDG-PET became a paradigmatic example of the superiority of functional over classic radiological imaging for the following reasons: (1) FDG-PET showed a higher sensitivity for nodal staging; (2) FDG-PET was clearly superior in detecting extranodal disease, both in the bone marrow and in other organs; and (3) FDG-PET had a consistent, large influence on HL staging, with a potential impact on treatment strategy in a substantial number of patients, and this became even more evident upon introduction of integrated FDG-PET/CT scanners [50]. In an early pioneer study using FDG-PET alone, CT and fused FDG-PET/CT were prospectively compared in 99 newly diagnosed HL patients. In nodal regions, the sensitivity of PET and PET/CT was higher than that of CT (92% and 92% vs. 83%). FDG-PET had more false-positive nodal sites than CT and FDG-PET/CT (1.6% vs. 0.7% and 0.5%). For evaluation of organs, FDG-PET and FDG-PET/CT had higher sensitivity (86% and 73%), while CT detected only 37% of involved organs. In conclusion, FDG-PET/CT upstaged 19% and downstaged 5% of patients, leading to a treatment modification in 9% of patients [30]. A recent study prospectively compared a cohort of 96 HL patients [51]. Similar to the previous study, radiologists and nuclear medicine physicians were blinded to the outcome of the other modality and to the clinical course of the patients. The breakdown of patients according to stage I to IV based on CT vs. FDG-PET/ CT was: 5 vs. 7, 49 vs. 37, 28 vs. 22, and 14 vs. 30, respectively. FDG-PET/CT changed the stage in 33 (34%) patients, 28% were upstaged and 6% downstaged. Upstaging was mainly caused by detection of new extranodal involvement (47 sites in 26 patients) including the bone marrow, spleen, and lung. Downstaging resulted from the absence of FDG uptake in enlarged nodes (<15 mm) in the abdomen and pelvis. FDG-PET/ CT led to a treatment modification in 20 (21%) of the patients, with 16 patients being allocated to more intensive treatment [51]. The role of bone marrow infiltration (BMI) in stage upgrading was even more evident in recent reports on the role of FDG-PET/CT in staging of patients enrolled in 117 the prospective UK National Cancer Research Institute RATHL clinical trial [52]. Out of 938 enrolled patients, FDG/PET-CT led to upstaging in 159 patients (14%) and downstaging in 74 (6%). The most frequent staging migration was from stage III to IV due to detection of disease spread to extranodal sites (ENS), most frequently in the bone marrow, lung, and others. In the cases of discrepant results, follow-up images confirmed the HL nature of the lesion detected by FDG- PET/CT only. CT is insufficient for BMI evaluation in HL, while PET/CT detects skeletal FDG uptake in 10–20% of patients [53, 54]. This observation changed the perception that BMI is a rare occurrence in HL. Most studies using BMB for HL detection in the bone report a BMI frequency of only 5–8% [55]. The use of iliac crest bone marrow biopsy as a surrogate for the whole bone marrow compartment has been challenged by frequent finding of focal FDG lesions in the bone marrow in patients undergoing PET/CT staging. In addition, one-sided BMI has been reported in nearly half of the HL patients undergoing bilateral bone marrow biopsies [56]. In a recent large retrospective study performed by the German Hodgkin Study Group, Voltin et al. showed a PET/CT- detected BMI in 129/832 (15%) patients, while BMB was positive in only 20 (2%) [57]. With the gold-standard reference of either a positive PET scan (which becomes negative in subsequent follow-up scans) or a positive BMB or both, the sensitivity, specificity, positive, and negative predictive values of PET to detect BMI were 99.25%, 100%, 100%, and 99.9%, respectively. In conclusion, PET/CT has higher sensitivity for BMI than conventional BMB [31, 57, 58]. Rare patients with an undetected BMI by PET/CT at baseline almost exclusively present with advanced-stage disease based on PET/CT. Thus, the added diagnostic information from BMB very rarely leads to changes in clinical management [31]. As far as the pattern of FDG uptake is concerned, only focal uptake, defined as a single spot of FDG uptake at the bone level visible in at least two PET/CT slices with an intensity of FDG uptake ≥ liver, is considered as a harbinger of BMI. On the other hand, patients with a diffuse A. Gallamini et al. 118 FDG uptake (with an intensity ≥ liver) had disease outcomes identical to patients without any FDG uptake [53, 54]. Finally, one of the most interesting technological progress in PET/CT is the measurement of metabolic tumor volume (MTV) with more sophisticated software counting all voxel contained in a single contoured tumor lesion. To overcome the so-called partial volume effect, only voxel with an activity higher than a given threshold are counted. By multiplying the number of counted voxels using a fixed coefficient, it is possible to calculate the MTV expressed in cubic centimeters. (Fig. 7.1) Upon identification of the best cutoff value with ROC curve analysis, Cottereau et al demonstrated that, in early stage HL, a MTV value higher than 147 cm3 could single out a smaller (46 vs. 157) patient subset with poor prognosis compared to unfavorable patients [59]: the 3-Y PFS was 71% vs. 84% [60]. Since the actual standard of care for early-stage HL is tailored to EORTC prognostic criteria or similar score systems, MTV could guide the treatment intensity of early-stage HL. However, standardization problems due to intrinsic variability of PET-extracted semiquantitative variables such as SUV (standardized uptake value), different protocols for patient scanning and image acquisition/reconstruction, as well as different thresholds of SUVmax still hamper the use of this biomarker for risk stratification and treatment guidance in HL [61]. 7.4.2 Early Assessment of Chemosensitivity Dimensional parameters providing readout of tumor growth have extensively been used in standard radiological imaging to assess therapeutic effects early during treatment using the so-called RECIST criteria [62]. However, the kinetics of tumor shrinkage and regrowth are not linear and might overtake the prognostic impact of tumor size variation. Patients with residual mass persisting at the end of treatment need longer follow-up for judging response to treatment [63–65]. FDGPET/CT is the ideal tool to assess viable neoplastic cells in the context of residual masses detectable with CeCT. Since metabolic silencing is immediately visible after chemotherapy [13], response assessment with FDG-PET could be performed during treatment, as early after one [66, 67] or two [13, 15, 16, 68–70] cycles of chemotherapy, both in early- and advanced-stage HL. Fig. 7.1 Metabolic tumor volume: calculation example and VOI drawing depending on software (By Kanoun et al.: Plos One 2015;10(10):e0140830 (by permission)) 7 Functional Imaging in Hodgkin Lymphoma Despite the high FDG affinity of neoplastic Reed-Sternberg cells attributed to the “Warburg effect” of neoplastic tissue [37] or an m-TOR- mediated increase of transmembrane GLUT-1 protein [71], the high performance of interim FDG-PET in predicting HL outcome probably relies on the high affinity for the tracer of nonneoplastic microenvironment cells, which account for more than 95% of the total cells present in HL tissue [18]. Several publications stressed the role of interim PET (iPET) in predicting ABVD treatment outcome in advanced-stage HL [13, 15, 66– 70]. In a meta-analysis by Terasawa et al., interim PET in advanced-stage HL showed a sensitivity of 43–100% and specificity of 67–100%, respectively [70]. iPET proved to predict treatment outcome also in early stage, albeit with conflicting results [16, 72–74] and a lower specificity and positive predictive value [74]. Two questions concerning the ideal time for early interim FDG-PET scanning are still unsettled: (1) what is the best time point for FDG-PET after chemotherapy administration, and (2) what is the ideal number of chemotherapy cycles before the early interim FDG-PET scan? As far as the point (1) is concerned, in mice undergoing FDG scan, the FDG uptake by neoplastic cells and reactive inflammatory macrophages was minimal 14 days after chemotherapy administration [49]. An earlier evaluation, immediately after chemotherapy, could coincide with the stunning of the cellular glucose metabolism by immediate effects of chemotherapy compromising the sensitivity of the test [75]. In a review on interim FDG-PET during early treatment, Kasamon concluded that the optimal time for performing interim PET during chemotherapy ranges between 7 and 14 days after chemotherapy [76]. The answer to point (2) could depend on the aggressiveness of the tumor and the efficacy of the chemotherapy. In HL, there is most evidence for the use of FDG-PET after two courses of chemotherapy. More recently, two observational prospective studies have been published, stressing the good overall accuracy of interim PET performed as early as after one single cycle of chemotherapy, with very high sensitivity and negative predictive value [66, 67] especially in early-stage disease [67]. 119 7.4.3 Final Response Assessment Between 1999 and 2001, several papers reported high sensitivity and specificity of FDG-PET in tumor response assessment. In a meta-analysis of 13 studies on 408 HL patients, Zijlstra and colleagues demonstrated a pooled sensitivity and specificity of PET in defining treatment outcomes of 84% and 90%, respectively [77] (Fig. 7.2). As a consequence, FDG-PET was proposed as the essential tool for the definition of treatment response in the majority of different FDG-avid lymphoma, including HL. The most recent definitions of CR, PR, SD, or progressive disease were integrated into the International Harmonization Project for treatment response in lymphomas [78] and the revised Lugano criteria [9]. The Deauville 5-point scale [79] has been used to quantify and standardize the residual FDG uptake [10]. The traditional concept of CR and CRu were abandoned, and the term complete metabolic response (CMR) was proposed instead; similarly, the old concept of partial remission (PR) based on dimensional criteria was replaced by partial metabolic response (PMR) in FDG- avid lymphoma. No metabolic response (NMR) was suggested for nonresponse or stable disease patients, while progressive metabolic disease (PMD) was proposed for clearly progressive patients. Traditionally, dimensional criteria were maintained for the rare non-FDG-avid lymphomas [9]. Preliminary reports showed a better accuracy in defining treatment response and long-term outcome of the 5-point Deauville scale (5-PS) over the International Harmonization Project (IHP) criteria, both in early and advanced HL [78, 80, 81]. Fallanca et al. in a small cohort of 101 patients including 35 advanced HL cases were able to show a better specificity, positive predictive value, and overall accuracy of 5-PS over IHP criteria (87% vs. 67%, 74% vs. 57%, and 86% vs. 76%, respectively). Therefore, the reduced number of false-positive outcomes in the end-of-treatment PET proved to spare a significant number of patients from unnecessary treatment. Despite the good response to therapy, treatment of HL can result in residual masses in up to 80% of patients by conventional staging modalities, which A. Gallamini et al. 120 Sensitivity (95% CI) de Wit, 2001 Hueltenschmidt, 2001 Mikhaeel, 2000 Naumann, 2001 Spaepen, 2001 Weirauch, 2001 Zinzani, 1999 0 0.2 0.4 0.6 0.8 1 1,00 (0,69-1,00) 0,95 (0,74-1,00) 1,00 (0,29-1,00) 1,00 (0,03-1,00) 0,50 (0,19-0,81) 0,67 (0,30-0,93) 1,00 (0,29-1,00) Pooled sensitivity = 0,84 (0,71 to 0,92) Chi-square = 15,87; df = 6 (p = 0,0145) Specificity (95% CI) de Wit, 2001 Hueltenschmidt, 2001 Mikhaeel, 2000 Naumann, 2001 Spaepen, 2001 Weirauch, 2001 Zinzani, 1999 0,78 (0,56-0,93) 0,89 (0,72-0,98) 0,92 (0,62-1,00) 0,86 (0,71-0,95) 1,00 (0,93-1,00) 0,80 (0,56-0,94) 1,00 (0,69-1,00) Pooled specificity = 0,90 (0,84 to 0,94) Chi-square = 17,96; df = 6 (p = 0,0063) 0 0.2 0.4 0.6 0.8 1 Specificity Fig. 7.2 Zijlstra unchanged. (a) Sensitivities and 95% confidence intervals for studies assessing the diagnostic accuracy of FDG-PET in patients with HD. (b) Specificity and 95% confidence intervals for studies assessing the diagnostic accuracy of FDG-PET in patients with HD. (Asterisk) The diamond represents the 95% CI of the pooled estimate (From Zijlstra 2006, by permission [77]) are most frequent in the anterior mediastinum [63, 65]. The original study by Jerusalem et al. [82] showed the superior accuracy of FDG-PET over CeCT in predicting long-term disease outcome in patients showing persisting FDG uptake. Many reports confirmed the superior performance of functional imaging in this setting. In 2008, Terasawa et al. systematically reviewed all studies published so far on this topic, reporting a pooled sensitivity for HL ranging between 43% and 100%, with a specificity ranging between 67% and 100% [83]. In the pre-PET era, consolidation radiotherapy had been used in advanced-stage HL showing radiological evidence of a residual mass persisting after chemotherapy [2]. The endof-treatment PET was proposed to deliver consolidation radiotherapy (cRT) only in PET-positive residual masses. As a consequence, the number of patients undergoing cRT at the end of treatment changed from 71% to 11% [22]. In the German Hodgkin Study Group trial HD 15, cRT was administered to patients having FDG-avid residual mass of more than 2.5 cm at the end of chemotherapy. About 30% of the patients showed a residual mass, and in about 10% the residual mass proved FDG avid. Comparing irradiated with nonirradiated patients, the 4-year PFS was 86.2% and 92.6%, respectively (p = 0.022). Overall, the NPV at the end of therapy was 94% [22]. Savage et al. reported very similar results in a retrospective analysis of 163 advanced-stage HL patients undergoing cRT avter ABVD chemotherapy only in the case of a residual FDG-avid mass of 2 cm or more at the end of chemotherapy. Patients with a PETnegative scan (n = 130, 80%) had a 3-year time to progression far superior to that of patients with a 7 Functional Imaging in Hodgkin Lymphoma 121 PET-positive scan (89% vs. 55%, p = 0.00001), with no difference between those having bulky or non-bulky disease. The NPV for end-of-treatment PET was 92% [84]. However, NPV at the end-oftreatment PET depends on the efficacy of chemotherapy, being so low as 86% with low-intensity regimen such as VEBEP [85]. 7.4.4 Interpretation Criteria 7.4.4.1 Interim PET Scan Early studies demonstrated that not all interim PET scans could be dichotomized as positive or negative; some patients had “equivocal” or “inconclusive” results showing residual FDG uptake defined as minimal residual uptake (MRU). MRU definition evolved from residual unspecific FDG uptake with intensity equal, or slightly superior to mediastinum [86], to an uptake with higher intensity, equal to that of the liver [79]. This was proposed with the aim to increase the specificity and reduce false-positive results in predicting treatment outcome [87]. These criteria have been generally accepted by imaging specialists and clinicians as a useful tool for visual interim PET assessment in lymphoma and have been incorporated in several guidelines and recommendation by academic institutions [9, 10, 88–90] (Fig. 7.3). The Deauville five-point scale (5-PS) has been retrospectively and prospectively validated in HL in four different studies [11, 12, 52, 81]. Prospective testing between national imaging core laboratories also showed good interobserver agreement in HL [91]. In standard treatment or Fig. 7.3 The Deauville 5-point scale (unchanged) (From Meignan M, Leuk Lymphoma 2009, by permission [79]; Barrington S: Eur J. Nucl Med Mol Imaging 2010;37:1824–1833) treatment intensification planned for interim PET-positive patients, a Deauville score (DS) of 3 represents a complete metabolic response (CMR). DS 3 also proved to be the most reproducible threshold when interpreting PET scans in lymphoma patients [52]. If treatment is to be de- escalated, a more sensitive threshold is preferred to avoid the risk of undertreatment [3, 7]. The use of a higher threshold for a positive interim PET scan was supported by the RATHL trial showing that the DS in PET-negative patients (DS 1 vs. DS 2 vs. DS 3) did not influence PFS, suggesting that DS 3 is likely to represent CMR with standard ABVD treatment [4]. To obtain more stable measures of residual activity in interim PET, the Leipzig/Germany group proposed a semiquantitative method for interim PET reading, using the SUVpeak of the residuum and the SUVmean of the liver rather than SUVmax [92]. Since the residual lesion detected in interim PET is often very small and a VOI of 1 ml too large, the SUVpeak was defined as the average value in the maximum SUV voxel and the three hottest adjacent ones [92]. 7.4.4.2 End-of-Treatment PET Scan The presence of a FDG-avid residual mass at the end of treatment represents a true diagnostic dilemma. As mentioned above, only half of the residual masses at the end of treatment in HL have been considered as a harbinger of persisting disease [93]. Primary mediastinal B-cell lymphoma is a rare disease often presenting in young females with isolated mediastinal bulky lesion and a good treatment outcome [94]. The disease Deauville score (DS) Score 1 no uptake Score 2 uptake ≤ mediastinum Score 3 uptake > mediastinum but ≤ liver Score 4: moderately ↑ uptake > liver Sensitive threshold Specific threshold Score 5 markedly ↑ uptake > liver and/or new sites of disease Barrington S: Eur J. Nucl Med Mol Imaging 2010;37:1824–1833 Meignan M. Leukemia & Lymphoma 2009;50(8):1257–1260 122 A. Gallamini et al. is biologically and clinically related to nodular 2. Appearance of new lesions or growth of one or more existing lesion(s) ≥ 50% at any time sclerosis HL, where the putative normal cell during treatment, occurring in the context of counterpart is a thymic B cell [95]. End-of- lack of overall progression (<50% increase) treatment PET scan in this disease is often associof overall tumor burden, as measured by SPD ated with false-positive results [96, 97]. A 5-PS of up to 6 lesions at any time during the treatthreshold between 4 and 5 has been proposed as ment [IR(2)]. Again a biopsy is strongly positive scan [98]. Moreover, only the associaencouraged: if as expected, the biopsy is negation of 5-PS score 5 in end-of-treatment PET and tive, the lesion(s) is/are considered negative high baseline total lesion glycolysis (TLG) in and should no longer be considered in the folbaseline PET showed a very poor prognosis [98]. lowing scans. In conclusion, patients with residual FDG uptake in the context of a nodal mass with bulky disease 3. Increase in FDG uptake of 1 or more lesion(s) without a concomitant increase in lesion size at baseline should undergo biopsy if salvage or number [IR (3)]. Increased immune activtreatment is considered [99]. ity at the site of tumor may manifest as an increase in FDG uptake. Therefore, by itself, 7.4.5 Treatment Response changes in uptake should not trigger an assignAssessment to Immune ment of PD with checkpoint inhibitors. Checkpoint Inhibitors Nonetheless, whenever feasible, a biopsy is advised. Immune checkpoint inhibitors (CPI) are a new class of antineoplastic drugs that proved very Despite an evident bias of subjectivity, a comactive in lung cancer, melanoma, renal carcinoma mon denominator in these three categories of IR [100–102], and other neoplastic disorders, includ- is a “stable” clinical situation of the patient. ing HL [20, 103]. In the last few years, the knowl- Moreover, another common recommendation in edge on the mechanism of action has been largely the follow-up of these three IR is to perform a unveiled. The activation of the PD-1 receptor on second PET scan 12 weeks after the first imaging the T-cell surface by its ligand PD-L1 expressed (Fig. 7.4). on the surface of the neoplastic cells or macrophages downregulates T-cell function, which normally controls the immune activity [104]. Due to 7.4.6 PET in Radiotherapy Planning this mechanism of action restoring the immune reactivity of the host against the tumor, the anti- Radiation therapy in HL is an essential therapeuneoplastic activity of CPIs could be delayed, thus tic tool in combined modality treatment (CMT) fueling a sustained inflammatory response which of early-stage disease and a useful tool to conpersists beyond the drug administration and after solidate chemotherapy treatment in a limited treatment end. The following criteria and catego- number of advanced-stage patients with a residries for immune response (IRC) in lymphoma ual mass at the end of chemotherapy. Radiation (LYRIC) have been proposed [105]: techniques have benefited from an impressive technological evolution. Extended fields devel1. Increase in overall tumor burden (as assessed oped for single modality treatment have been by sum of the product of the diameters [SPD]) replaced by more conformal fields designed for of ≥ 50% of up to 6 measurable lesions in the CMT, encompassing the initially macroscopifirst 12 weeks of therapy, without clinical cally involved tissue volumes in early-stage disdeterioration [IR(1)]. A biopsy is advisable, ease and bulky masses and/or residual masses but when this is not possible, a second scan after chemotherapy in advanced disease [106– 12 weeks after the initial determination of IR 109]. These changes led to dramatic decreases in should be planned. the volume of normal tissue being irradiated and 7 Functional Imaging in Hodgkin Lymphoma 123 a parallel reduction in the risk of serious long- term sequelae of RT. A more accurate geometry for radiation field delineation also demands a higher accuracy of the imaging technique used. As FDG-PET has been shown to be more accurate for HL staging, it is by implication also more precise in defining the initially involved regions to be irradiated in patients with early-stage disease. No diagnostic modality has a 100% overall accuracy, and the delineation of the lymphoma volume must be based on the diagnostic information available, including FDG-PET/CT of both anatomy and physiology of the disease [110– 112]. In 2013, the International Lymphoma Radiation Oncology Group (ILROG) identified the residual gross tumor volume (GTV) as the first imaging target to be delineated in post- chemotherapy FDG-PET to be redrawn in the co-registered images of pre-chemotherapy PET scan [113]. Then, clinical target volume (CTV) should be identified by contouring the original GTV in pre-chemotherapy FDG-PET. Finally, especially when the target is moving, the internal target volume (ITV) should be delineated moving from CTV plus a margin taking into account uncertainty in size, shape, and position of the CTV in the patient. The optimal tool to obtain ITV is using a 4D CT simulator and, as a second choice, by fluoroscopy. Margins of 1.5–2 cm in cranio-caudal direction are commonly chosen in the chest or upper abdomen. Finally, the planned target volume (PTV) is calculated to delineate the IR1: Increase in overall tumor burden (by SPD) of ≥50% of up to 6 measurable lesions in the first 12 weeks of therapy, without clinical deterioration IR1 Baseline CT Restaging CT 1-3 wks Restaging CT 2-7 wks Restaging CT 3-13 wks Courtesy H. Jacene Fig. 7.4 Type 1, type 2, and type 3 IR (indefinite response) according to LYRIC criteria (From Cheson. Type 1, type 2 and type 3 LYRIC type of response. Blood 2016 [105]: courtesy of B. Cheson). IR1: Increase in overall tumor burden (by SPD) of ≥50% of up to six measurable lesions in the first 12 weeks of therapy, without clinical deterioration (Courtesy H. Jacene). IR2: Appearing of new lesions; or growth of oneor more existing lesion(s) ≥50%; at any time during treatment; occurring in the context of lack of overall progression (<50% in increase) of overall tumor burden, by SPD of up to six lesions at any time during the treatment (Courtesy H. Jacene). IR3: Increase in FDG uptake of one or more lesion(s) without a concomitant increase in lesion size or number (Courtesy L. Schwartz) A. Gallamini et al. 124 IR2 IR2: Appearance of new lesions; or growth of one or more existing lesion(s) of ≥50%; at any time during treatment; occurring in the context of lack of overall progression (<50% increase) of overall tumor burden, by SPD of up to 6 lesions at any time during the treatment. May 2015 IR2 October 2015 December 2015 Courtesy H. Jacene Fig. 7.4 (continued) 7 Functional Imaging in Hodgkin Lymphoma 125 IR3: Increase in FDG uptake of one or more lesion(s) without a concomitant increase in lesion size or number IR3 L R 50 pixels Courtesy L. Schwartz Fig. 7.4 (continued) radiation fields as function of immobilizing ate analysis predictive of progression-free surdevices, body site, and patient cooperation. In vival (PFS) [121]. Different groups [122–124] early-stage HL undergoing CMT pre-and a large meta-analysis of the published literachemotherapy, PET/CT should be acquired with ture including also non-Hodgkin lymphoma [125] the patient in the same position to be used for demonstrated that interim PET (iPET) before RT. Relatively limited clinical data are available ASCT in r/r HL had a predictive value (PV) indeon CTV definition by FDG-PET for RT planning pendent from other RF. The impact was similar to in HL [114, 115]. If extended-field irradiation is that during first-line ABVD treatment, where still used, the impact of FDG-PET is not expected iPET proved the prognostic marker with the highto be very large since additional involvement est PV, irrespective of other RF included in the found on FDG-PET will often be included in International Prognostic Score (IPS) [15]. More large treatment fields anyway [116, 117]. With recently, semiquantitative reading of PET with modern, more conformal radiotherapy, changes metabolic tumor volume (MTV) calculation on due to FDG-PET have been shown to be signifi- the scan performed at the time of HL relapse cant [118, 119]. proved to be the strongest predictor of treatment outcome in r/r HL [126]. Curiously, MTV computed on the FDG-PET performed at relapse and 7.4.7 PET for Response Prediction interim PET performed immediately before During Salvage Treatment ASCT behaved as independent prognostic factors, and the former improved the PV of the latter. High-dose chemotherapy (HDC) followed by Overall, the two FDG-PET scans performed in autologous stem cell transplantation (ASCT) different time points during salvage treatment for remains the best treatment option for relapsed/ r/r HL were able to recapitulate 4 out of the 5 refractory Hodgkin lymphoma (r/r HL) [120]. RisPACT factors: MTV in baseline PET portrays More recently, an international consortium mod- tumor burden (bulk and stage IV disease), while eled r/r HL (the RisPACT consortium) retrospec- iPET is able to detect a low chemosensitivity tively identified stage IV, ECOG performance (inadequate response to treatment/chemotherapy status ≥1, bulky nodal lesion >5 cm at relapse, resistance and possibly an inadequate immune time to relapse ≤3 months, and an inadequate response by the host) [127]. The 3-year EFS rates therapy response, assessed with a CT or PET/CT for patients with low MTV/negative pretransplant before ASCT, as the sole risk factors, in multivari- PET, low MTV/positive pretransplant PET, high A. Gallamini et al. 126 1.0 A. PET neg and low MTV, n=41, censored 38 0.8 B. PET pos and low MTV, n=7, censored 6 65 patients valuable N=65 BV x 3 BV x 3 Overall 49/65 (75%) of the patients obtained PET-negativity before ASCT N=18 BV x 3 DS 1-2 PET PET MTV MTV N=45 ASCT N=1 DS 3-5 N=31 *auglCE x2 Lost to f. up N=1 DS 1-2 ASCT DS 3-5 ASCT Event free survival PET-adapted sequential therapy with BV and augICE induces FDG-PET normalization in 76% of patients with relapsed/ refractory HL 0.6 C. PET neg and high MTV, n=8, censored 3 0.4 0.2 PET N=47 N=14 *augICE (augmented ICE). : Ifosfamide 5 gr. /m2 with Mesna 5 gr./m2) day 1 Carboplatin [maximum dose 800 mg]) on day 3, Etoposide 200 mg/m2 every 12 hours x 3 from day 1; DS: Deauville Score PET; positron emission tomography. Moskowitz AJ, et at. Blood. 2017;130:2196-203. 0.0 D. PET pos and high MTV, n=3, censored 0 0 10 20 30 40 50 Months Fig. 7.5 Baseline and interim PET to predict treatment outcome in relapsed/refractory Hodgkin lymphoma (From Moskowitz AJ Blood 2017, by permission [126]) MTV/negative pretransplant PET, and high MTV/ positive pretransplant PET were 93%, 86%, 38%, and 0%, respectively (p < 0.0001) [126] (Fig. 7.5). 7.4.8 ET for Follow-Up of HL P Patients in Complete Remission The impact of surveillance imaging tests (CT, FDG-PET/CT) during follow-up of lymphoma patients in CR after treatment is still a matter of debate. In general, the probability of detecting relapse during monitoring for disease recurrence depends on the probability of relapse of the disease in the population being tested, as well as the sensitivity, specificity, and the frequency of the test [128]. The prevalence of relapse in a HL patient in complete remission at the end of treatment is rare, corresponding to one event per 68 visits in HL [129]. Moreover, the risk of relapse could depend on a number of clinical parameters associated with disease relapse as follows: (1) the presence of clinical symptoms, (2) poor chemosensitivity of the tumor at interim evaluation, (3) the preferred anatomical pattern of recurrence of a given lymphoma subtype, as well as (4) a residual mass at the end of treatment [130]. Up to 80% of relapses in HL are associated with clinical symptoms [129, 131]. Zinzani et al. investigated the role of surveillance FDG-PET performed every 6 months for 4 years after CR [132]. Overall, 778 scans were evaluated in a cohort of 160 HL patients. In 11/778 scans (1.4%), PET was classified as positive, mainly in the first 18 months after CR. All these patients underwent a confirmatory biopsy: 6/11 were proven positive, mostly in patients having an interim-positive PET scan. A total of 51 relapses in 160 HL patients were detected: all 51 by PET/CT, 37 by CT, and 35 by clinical symptoms. However, 778 PET/CT scans were needed to detect 14 relapses earlier than CT or other methods. Jerusalem et al. performed FDG-PET every 4–6 months for 3 years in 36 HL patients who were in CR after ABVD for a total of 139 scans. Six false-positive studies, and no false-negative studies, were found. In the five positive studies, FDG-PET preceded the relapse at a median of 3.5 [1–9] months [133]. In 2012, El-Galaly et al. published a retrospective study in a cohort of 299 HL patients in CR after ABVD, in which surveillance PET scan was used in asymptomatic patients (routine scans n = 211) or for patients suspected of harboring an impending relapse (clinically indicated, n = 88). The true positive rates of routine and clinically indicated scans were 5% and 13%, respectively. The overall positive and negative predictive values were 28% and 100%, respectively. The estimated cost per routinely diagnosed relapse was 50,778 US $ [134]. In conclusion, surveillance FDG-PET cannot be recommended as a routine follow-up procedure for HL patients in complete remission after first-line treatment; instead, this 7 Functional Imaging in Hodgkin Lymphoma should be considered in rare cases of patients with high risk of relapse without signs or symptoms of disease. 127 chemotherapy only arms were stopped prematurely after a futility interim analysis predicted failure of meeting the primary endpoint, which was PFS non-inferiority [136]. The final analyses confirmed a loss of disease control when radio7.5 PET Response-Adapted therapy was omitted, even though the difference in PFS was only clearly clinically relevant in patients Therapy without risk factors [7]. In the GHSG HD16 study 7.5.1 Early-Stage HL for patients with early-stage disease and no risk factors, patients were randomized to either stanMore than 90% of early-stage HL patients are dard therapy with 2 × ABVD + 20 Gy radiothercured with standard therapy. These patients still apy or an experimental arm where PET-negative have a reduced life expectancy due to treatment- patients after 2 × ABVD would receive no further related morbidity including second cancers and treatment. After a median follow-up of 47 months, cardiopulmonary disease. In fact, early-stage HL the estimated 5-year PFS for early PET-negative patients more often die from late effects of treat- patients was 93.4% (90.4–96.5) with standard ment than from the disease itself [135]. A number treatment and 86.1% with chemotherapy only. The of trials have investigated such PET-response- hazard ratio was 1.78 with a 95% CI ranging from adapted therapy in early-stage HL. The UK 1.02 to 3.12, including the non-inferiority margin National Cancer Research Institute (NCRI) of 3.01. The PFS difference resulted from a signifiLymphoma Group RAPID trial for early-stage cant increase in disease recurrences with infield patients as well as the German Hodgkin Study recurrence rates of 2.1% vs. 8.7% (p = 0.0003); Group (GHSG) HD16 randomized trial investi- there was no relevant difference regarding outfield gated non-inferiority of reducing treatment inten- recurrences (3.7% vs. 4.7%, p = 0.55). There was sity by omitting radiotherapy interim PET-negative no difference in the estimated 5-year overall surearly-stage patients. The experimental arms of vival in the per-protocol population (98.1% in the EORTC/GELA/FIL H10 study also omitted radio- standard arm vs. 98.4% in the chemotherapy-only therapy in interim PET-negative patients while arm) [137]. escalating from standard ABVD to more intensive In the H10 study, PET2-positive patients in the BEACOPPesc followed by radiotherapy in PET- experimental arm (including both favorable and positive patients. Both the RAPID trial and the unfavorable risk groups) had their treatment intenH10 trial failed to demonstrate non-inferior PFS in sified with a shift to two cycles of more intensive the chemotherapy-only arms. In the UK RAPID chemotherapy (BEACOPP escalated) followed by study, patients who were PET negative after three radiotherapy. In the PET2-positive patients, PFS cycles of chemotherapy were randomized to either of patients with a BEACOPP-intensified chemoradiotherapy or no further treatment (NFT). At a therapy was significantly better when compared median follow-up of 3 years, the PFS difference in with the standard arm where patients were treated the RAPID trial was 3.8% (95% CI, 8.8–1.3) with less intensive chemotherapy followed by favoring the radiotherapy arm, thus failing to meet radiotherapy (5-year PFS 90.6% vs. 77.4%, HR the predefined margin of non-inferiority of 7%. 0.42 with 95% CI 0.23–0.74) [7]. This difference There was no difference in overall survival (OS) was mainly due to improved PFS of patients in the between the two treatment arms [3]. The European unfavorable risk group who received intensified H10 trial stratified patients in favorable and unfa- chemotherapy. Even without knowing the results vorable subgroups, according to standard risk fac- of the German HD16 study, we can conclude from tors for early-stage HL [7]. All patients had an the RAPID and H10 studies that omitting radioFDG-PET after two cycles of chemotherapy therapy in good-risk (PET2-negative) patients (PET2). In the experimental arms, PET2-negative results in a modest loss of disease control (PFS), patients were given chemotherapy alone, but the while there is no difference in OS. A. Gallamini et al. 128 7.5.2 Advanced-Stage HL showed similar results from escalation to eBEACOPP in PET-positive patients after two cycles Around 70% of advanced-stage HL patients can of ABVD (3-year PFS 60%). They also showed be cured with six cycles of ABVD with or without no improvement of outcomes from consolidative consolidation radiotherapy, which is the standard radiotherapy to initially bulky masses (>5 cm) in first-line therapy in most centers. BEACOPPesc patients who were PET2 negative and remained cures 85–90% of patients if given upfront, but con- posttreatment PET negative [17]. In the German cern regarding acute toxicity and second neopla- HD18 study, all patients with advanced-stage HL sias is the reason why a number of centers are had two cycles of BEACOPPesc followed by reluctant to use this regimen as standard therapy FDG-PET. Patients in the standard arm received [138]. Numerous trials have investigated PET- eight cycles of BEACOPPesc, but half way durresponse-adapted therapy for advanced-stage HL ing the study, the duration of standard treatment patients. Three non-randomized trials used early was abbreviated to six cycles as a result of the treatment intensification with BEACOPPesc analysis of the German HD15 study. In the exper(The Italian GITIL HD 0607, the US SWOG imental arm, PET2-negative patients (Deauville S0813 and the UK RATHL trial) or even high- 1–2) only received an additional two cycles of dose chemotherapy with autologous stem cell sup- BEACOPPesc. The final analysis showed that in port (The Italian HD0801 FIL trial) in patients PET2-negative patients, a total of four cycles was who were still PET positive after two cycles of non-inferior to six cycles in terms of 5-year PFS ABVD. The randomized German HD18 trial (90.8% vs. 92.2%) and importantly was associtested abbreviation on BEACOPPesc therapy ated with significantly less acute and late toxicity based on PET results after two therapy cycles. The [140]. PET2-positive patients continuing eBEAFrench AHL 2011 trial was also a BEACOPPesc- COPP still had very high 3-year PFS of 87.6% based randomized trial with treatment modifica- (95% CI 83.0–92.3), illustrating that the positive tions based on PET after both two and four cycles. predictive value of interim FDG-PET depends on The UK RATHL study included 1214 patients the treatment setting. A subsequent analysis with stage IIB–IV or stage IIA with high-risk fea- showed no differences in outcome between tures who received two cycles of ABVD followed patients in the standard arm who had a Deauville by FDG-PET. PET2-negative patients (Deauville score of 1–2 and those with a Deauville score of scores 1–3) were randomized to either continued 3 (the latter would in many other studies be conABVD (total of six cycles) or treatment without sidered PET negative, but in HD18 regarded as bleomycin (AVD), for 4 cycles. The analyses of PET positive). This indicates that abbreviation of the PET2-negative patients showed no difference BEACOPPesc therapy in early PET-negative in PFS between the two randomization arms patients should be done in those having a PET2 (3-year PFS 85.7% vs. 84.4%) [4]. Even though Deauville score of 3 as well as in patients with in the primary analysis the results fell short of the Deauville score of 1 and 2 [141]. The French specified non-inferiority margin, an updated AHL2011 study aimed to assess whether interim analysis showed that with extended follow-up the FDG-PET could identify good-risk patients to be study had met its primary endpoint of PFS non- given de-escalation treatment BEACOPPesc inferiority [139]. upfront. A total of 823 patients were randomized PET2-positive patients received more inten- to the standard arm (n = 413) and the experimensive chemotherapy with an additional four cycles tal arm (n = 410). After a median follow-up of of BEACOPP14 or BEACOPPesc, resulting in a 50.4 months, the 4-year progression-free survival 3-year PFS of 68%, comparing favorably with (PFS) for the experimental arm was 87.1% and historical controls from observational studies in for the standard arm 87.4% with no difference in which ABVD was continued in PET2-positive OS, demonstrating that treatment intensity can be patients [4, 12, 30]. The Italian single-arm GITIL/ safely reduced from BEACOPPesc to ABVD in FIL HD0607 (stage IIB–IV patients) study PET2-negative patients [142]. 7 Functional Imaging in Hodgkin Lymphoma Thus, in advanced-stage HL, early interim PET can be used to de-escalate therapy such as reducing the number of BEACOPPesc cycles, reduction of intensity from BEACOPPesc to ABVD as well as omission of bleomycin from ABVD in PET2negative patients. At the same time, intensification to BEACOPPesc should be considered with insufficient initial PET response to ABVD. 7.5.3 Post-chemotherapy PET/ CT-Driven Consolidation Radiotherapy In advanced HL, radiotherapy is used less frequently than in early-stage HL and usually only to residual masses. CT cannot discriminate between a residual mass with viable lymphoma cells and a residual mass consisting only of fibrotic tissue. However, since PET/CT cannot detect microscopic disease, it was necessary to perform studies to investigate whether a PET- negative residual mass requires radiotherapy or not. The mature results of the German HD15 trial shed light on this for patients treated with BEACOPP. In the HD15 study, consolidation radiotherapy was given only to those patients having a PET-positive single residual mass of more than 2.5 cm, which was encompassable in a single field of radiotherapy. The remaining majority of patients who did not receive radiotherapy had a relapse-free survival of 94% after 1 year, indicating that radiotherapy can be safely omitted in advanced-stage HL patients who are PET negative after the end of BEACOPPesc [22, 143]. A retrospective analysis from the British Columbia Cancer Agency addressed the same situation for patients treated with ABVD. The authors reported a 10-year experience with advanced-stage HL patients having residual masses >2 cm after chemotherapy undergoing PET/CT (n = 163). Only patients with a positive posttreatment PET/CT received radiotherapy. At the end of treatment, 316 patients had residual masses larger than 2 cm undergoing PET/CT. Of those, 264 (83.5%) were FDG-PET negative, none of whom received RT, and 52 (16.5%) were FDG-PET positive, of whom 79% (n = 41) 129 received consolidative RT (30–35 Gy). With a median follow-up for living patients of 4.6 years (range 0.6–13.5 years), the 5-year freedom from treatment failure (FFTF) for the whole cohort was 83%, and the 5-year OS was 94.5%. Not surprisingly, patients with a negative posttreatment FDG-PET had a superior 5-year FFTF compared to those with a positive scan (89% vs. 56%, respectively). In the posttreatment FDG-PET- negative group, there was no difference in outcome comparing bulky (n = 112) and non-bulky (n = 152) subgroups (5-year FFTF 89% vs. 88.5%, respectively). Similarly, when the analysis was restricted to FDG-PET-negative patients with a bulky mediastinal mass at diagnosis (n = 102), outcomes were excellent (5-year FFTF 89%; 5-year OS 96%) [84]. These results support the omission of radiotherapy in advanced-stage HL patients who achieve a PET-negative remission after six cycles of chemotherapy. 7.5.4 PET/CT-Adapted Therapy in Relapsed HL For HL patients in first relapse, a number of risk factors predict outcome after high-dose chemotherapy with autologous stem cell support (HD + ASCT) [121]. Two important factors are the duration of remission prior to relapse and the response to induction therapy. A number of studies have shown that FDG-PET performed after induction therapy and before HD + ASCT can predict the long-term remission after salvage [144–146]. These studies report a poor long-term PFS in patients who are FDG-PET positive after induction chemotherapy (31–41%), compared to a PFS of 73–82% in patients who reach a PET- negative remission before HD + ASCT. A study from the Memorial Sloan Kettering Cancer Center investigated a PET-guided approach where FDGPET-positive patients after the standard induction (ICE, ifosfamide, carboplatin, etoposide) instead of proceeding to HD + ASCT were given a noncross-resistant regimen consisting of four biweekly doses of gemcitabine, vinorelbine, and liposomal doxorubicin (GVD) before HD + ASCT. Patients who were FDG- PET 130 p ositive after ICE but became FDG-PET negative after GVD had similar outcomes compared to those who were PET negative after ICE [147]. A number of studies demonstrated a high prognostic value of pretransplant FDG-PET/CT before alloSCT with reduced intensity [148– 150]. Two studies suggest that FDG-PET/CT may have a role in guiding the use of donor lymphocyte infusions after allogeneic stem cell transplantation [151, 152]. A. Gallamini et al. nitions for complete response (CR) and partial response (PR), stable disease (SD), progressive disease (PD), and relapsed disease (RD). Since these recommendations were based on CT scanning, they included the category of complete remission unconfirmed (CRu), first introduced in the Cotswold classification [24], referring to patients with a persistent mass with size reduction following treatment which, represented fibrosis, rather than viable lymphoma. PET scans were initially considered as an adjunct to lymphoma assessment in about 1990. 7.6 Toward Revised Criteria Their added value was first demonstrated by Juweid et al. [153]. They compared the outcome for PET Scan Interpretation of 53 patients with diffuse large B-cell lymphoma Juweid et al. first demonstrated that PET-based using either the NCI-WG response criteria alone response improved predictability compared to or with the incorporation of PET. Progression- criteria relying on CT. They demonstrated that in free survival was similar regardless of whether patients with diffuse large B-cell NHL and a the patient had a CR or PR based on CT criteria, residual mass posttreatment, a lack of FDG avid- as long as the mass was not FDG avid. Thus, not ity correlated closely with a CT-based CR for the only was the accuracy of response assessment end-of-treatment evaluation [153]. These obser- improved with PET, but the misleading term CRu vations were subsequently confirmed, leading to was eliminated as a response category. the incorporation of PET into standardized Along with the validation of the above obserresponse criteria for patients with DLBCL and vations, numerous other studies demonstrated the HL [78]. These initial studies of PET used visual superior sensitivity and specificity of PET comassessment using the mediastinal blood pool as pared with CT mandated revised response critethe comparator and formed the basis of the rec- ria. Thus, in 2007 the International Harmonization ommendations of the International Harmonization Project published recommendations that incorpoProject in lymphoma [78]. Efforts toward a more rated PET [78]. These were primarily for HL and reliable and reproducible approach resulted in the DLBCL as data with FDG-PET in other histo5-point Deauville criteria which are more accu- logic subtypes were limited. rate with greater interobserver concordance and a In the ensuing years following publication of higher positive predictive value (PPV) [11]. One the 2007 criteria, a large body of data demonconsequence of this improvement was the Lugano strated the role of FDG/PET in follicular lymclassification currently considered the standard phoma (FL) as well as other histologies [155]. for staging and response assessment for all FDG- Whereas PET interpretation in the 2007 criteria avid lymphomas [9, 10]. was purely visual, using mediastinal blood pool as the reference standard, the newly created Deauville 5-point scale (D5-PS) used the hepatic 7.6.1 Qualitative vs. blood pool and was more reproducible [79]. In Semiquantitative Assessment 2014, the Lugano classification was published recommending FDG PET/CT as standard for 7.6.1.1 From Anatomical to Functional staging of FDG-avid histologies [9, 10]. Several Imaging studies in HL demonstrated the improved sensiIn 1999, the National Cancer Institute-sponsored tivity of FDG/PET compared with bone marrow Working Group (NCI-WG) published the first biopsies [31, 52, 57, 156]. Thus, in the Lugano uniformly adopted response criteria for lymclassification, trephine biopsies were no longer phoma [154]. These included standardized defi- required in the routine staging of HL. The Lugano 7 Functional Imaging in Hodgkin Lymphoma classification also recommended the D5PS for interpretation of FDG/PET for assessment of response to treatment assessment. The change from the binary IHP criteria to the five-point DS is associated with greater interobserver reproducibility and provides greater flexibility to modify the threshold between a good and a poor response according to the clinical context and/or the proposed treatment strategy. The DS is now uniformly adopted and is of particular importance in risk-adapted therapeutic strategies. The group that requires particular attention are the DS5 patients whose outcome differs significantly even from DS4 [4] in advanced disease, but has been yet demonstrated in those with limited-stage disease. 7.6.1.2 T oward New Criteria for Response Assessment of New Drugs The availability of newer effective treatment led to issues in interpretation of response and disease progression due to the occurrence of flare reactions. The most notable examples are immunomodulatory agents that stimulate the immune system resulting in a flare reaction, particularly lenalidomide [157–160]. Similar effects were observed for rituximab [161, 162], brentuximab vedotin [163], ibrutinib [164], and idelalisib [165], respectively. In HL, the use of checkpoint inhibitors can induce a flare reaction that may be confused with progressive disease [20]. This potential clinically significant problem led to publication of the lymphoma response to immunomodulatory therapy (LYRIC) criteria [105] (see Chap. 4). These recommendations use a provisional term of indeterminate response to categorize various types of flare reactions. Thus, patients in whom a flare reaction is considered may remain on treatment until progressive disease is confirmed by biopsy or by continued growth, or evidence of deterioration. 7.6.1.3 Biomarker Integration in Response Criteria Despite the sensitivity of PET-CT scans, the negative predictive value remains imperfect. An increasingly recognized problem is that relapse occurs not infrequently, even in patients consid- 131 ered to be in a CMR following therapy. In the RAPID trial [3], patients with stage I/IIA non- bulky disease underwent PET after three cycles of ABVD. Those with a negative PET were randomized to IFRT or no further therapy. In patients considered in mCR, there was an apparent correlation between the maximum transverse diameter of the tumor and the likelihood of recurrence, with a threshold of 5 cm. Thus, assays that are able to detect minimal residual disease may be a useful adjunct, not only in response assessment but also in distinguishing a flare reaction from progressive disease. Circulating DNA assays have been used in patients with NHL to predict outcome and are approved by the FDA [166]. Only recently has this technology been applied to HL. Van Eijndhoven et al. [167] suggested that classical HL-related miRNA levels in circulating EVs may reflect the presence of tumor tissue and may provide a marker for therapy response and relapse monitoring in HL patients. Rossi et al. [168] using a sensitive next-generation sequencing technique demonstrated the potential for monitoring patients with HL lymphoma. In a study of 102 Hodgkin lymphoma patients treated with ABVD, interim PET, pretreatment CD68+ cell counts, and the presence of B symptoms were independently associated with PFS [169]. Therefore, the evaluation of CD68+ cell counts and B symptoms at diagnosis was suggested to help identify low-risk patients regardless of a positive interim PET result. Agostinelli et al. [170] provided evidence for an interaction between the microenvironment and PET. Although PET after two cycles of therapy predicts outcome in HL, 10–15% of patients still relapse. When interim PET after two cycles was combined with pretreatment environmental markers including PD-1 and CD68 in Micro Environment cells and STAT-1 in HRS cells in a Classification and Regression Tree (CART) analysis, PET2-negative patients could be distinguished into three risk groups with markedly different outcomes. 7.6.2 Interim PET The use of quantitative techniques has been explored in DLBCL to improve on the accuracy A. Gallamini et al. 132 of visual assessment. Change in the maximum SUV (ΔSUVmax) in tumor before and after treatment has been evaluated as a measure of response. Lin et al. [171] and Itti et al. [172] performed receiver operator curve (ROC) analysis in 92 patients with DLBCL who underwent PET scan after two cycles of therapy, and 80 patients were scanned after four and identified the optimum thresholds for percentage change in SUVmax for predicting event-free survival (EFS). The ΔSUVmax better predicted PFS, compared with standard visual analysis. Biggi et al. [173] provided data from a retrospective analysis to suggest that incorporating semiquantitative analyses with visual interpretation improved predictive value of interim and end-of- treatment PET. Unfortunately, despite the fact that other groups have also reported that ΔSUVmax predicts response, the thresholds vary widely among studies. Thus, it is not clear that this technique is ready for general application until there is improved consistency in scanning protocols, matching conditions for serial scans, as well as proper calibration and scanner maintenance. The optimum cutoff is also likely influenced by timing, with a tendency for a higher cutoff later during treatment. Clinical correlation is also critically important. 7.6.3 End-of-Treatment PET As first reported by Juweid et al. [153] and further recommended in the Lugano classification [9, 10], PET-CT is the standard of care for remission assessment in FDG-avid patients. PET allows for better discrimination between fibrosis and residual tumor, reducing the implementation of additional therapy. The high-level accuracy for PET was reported in patients with advanced HL following ABVD [174]. Another example is the German HD15 trial in which patients with a residual mass of at least 2.5 cm underwent PET [22]. If negative, they received no further therapy. Patients with a positive scan underwent radiation therapy. The outcome of the group with a residual mass that was not FDG avid was similar to those without a residual mass. Whether the size of the residual mass is clinically important is controversial. In a subsequent subset analysis of the German HD 15 trial [175]), those with a positive end-of-treatment PET and a decrease in the size of the residual mass <40% had a particularly poor outcome with a relapse rate in the first year of 23.1% compared with 5.3% for those with a greater decrease. For patients with a residual mass following treatment of HL and for whom additional therapy is being considered, whether a biopsy is recommended is controversial as it is often falsely negative in HL due to the effects of treatment and sclerosis of the tumor. 7.7 FDG-PET/MRI In 2014, a preliminary report was published comparing PET/MRI and PET/CT in a head-to-head for tumor staging in a cohort of 50 patients affected by miscellaneous cancers undergoing PET/CT with a non contrast-enhanced low-dose CT for attenuation correction at 120 KeV with 10 mA, followed 20 min later by PET-MRI [176]. All patients underwent whole-body PET/CT after a single intravenous injection of PET tracers 18F- FDG, 68Ga-DOTATATE, or 18F-fluoro-ethyl- choline (18FFECH) according to a standard clinical protocol performed on an integrated 64-slice PET/CT scanner (Discovery VCT; GE Healthcare). PET/MRI imaging was performed using a Siemens 3T Biograph mMR system with an integrated PET system within the MR gantry, which allows simultaneous PET and MR acquisitions without having to reposition the patient. Two hundred twenty-seven FDG-avid lesions were found: 225 were detected on PET/CT, and all the 227 on PET/MRI. Overall, anatomic localization was superior in 5.1% of the cases in PET/ MRI modality compared with PET/CT; this was attributed to the established superior soft tissue contrast seen in head and neck, pelvis, and colorectal cancer patients. More recently, advances in magnetic resonance imaging (MRI) technology allowed the introduction of “functional” MRI, such as whole-body diffusion- weighted MRI (WB-DW-MRI). The latter could improve the sensitivity of tumor staging by standard MRI, thanks to a higher tumor-to- 7 Functional Imaging in Hodgkin Lymphoma background contrast, and of tumor restaging, thanks to a different apparent diffusion coefficient of the necrotic post-therapy tissue vs. that of the viable, pre-therapy, tumor lesion [177]. Herrmann et al. prospectively evaluated the overall accuracy of FDG-PET/CT, FDG-PET/MRI, and WB-DW-MRI for lymphoma staging and restaging in a cohort of 61 patients, including 21 cases of HL [178] undergoing sequential scanning with these three imaging techniques [178]. A total of 82 examinations were performed: 14 for staging and 68 for restaging, during (n = 14) or after chemotherapy (n = 19) and during follow-up (n = 35). Most examinations were performed in HL (n = 28) or diffuse large B-cell lymphoma (DLBCL; n = 26). FDG-PET/CT was used as reference method for assessing the performance of the other two techniques. One hundred thirteen lesions were found in lymphoma staging: FDG- PET/MRI detected all of them, while WB-DW-MRI detected only 64.6% of the lesions. FDG-PET/CT and FDG-PET/MRI detected the same number of lesions during interim (n = 16), end-of-therapy (n = 12), and surveillance (n = 47) scanning. On the other hand, WB-DW-MRI detected 56.3%, 50.0%, and 78.7%, respectively. The authors concluded that FDG-PET/CT and FDG-PET/MRI had a comparable diagnostic performance, while WB-DW- MRI could be preferred during patient follow-up as the latter had a comparable sensitivity to FDGPET/CT or FDG-PET/MRI in detecting residual, persisting disease. 7.8 Future Perspectives 7.8.1 Other Tracers FDG is a glucose analogue, and FDG uptake reflects the level of glucose metabolism in the tissue. However, like other cancers, lymphoma is characterized by deregulated cell cycle progression, and most anticancer drugs are designed to inhibit cell proliferation. Thus, a tracer enabling imaging of cell proliferation could be useful for both initial characterization and treatment monitoring of the disease. FDG uptake is somewhat correlated with cell proliferation, but this correla- 133 tion is weakened by a number of factors, including FDG uptake in nonmalignant lesions as a result of inflammation or infection. The nucleoside [11C]thymidine was the first PET tracer to specifically address cell proliferation. Early studies suggested that [11C]thymidine could determine both disease extent and early response to chemotherapy in aggressive NHL patients [179, 180]. However, the short 20-min half-life of 11C along with rapid in vivo metabolism limited its clinical application. The thymidine analogue 3′-deoxy-3′-[18F]fluorothymidine (FLT) offers a more suitable half-life of 110 min and is stable in vivo [181]. A pilot study of seven patients showed that FLT-PET can sensitively identify lymphoma sites and distinguish aggressive from indolent NHL [182, 183], although less sensitive than FDG [184]. Furthermore, preclinical studies suggested a potential of FLT for imaging in early response to treatment in lymphoma [185]. Increased uptake of amino acids reflects the increased transport and protein synthesis of malignant tissue [186]. This observation provides the rationale for PET imaging of amino acid metabolism with the labeled amino acids L-[methyl-11C]methionine (MET) and O-2-[18F] fluoroethyl-L-tyrosine (FET). Nuutinen et al. [187] studied 32 lymphoma patients and found MET-PET to be highly sensitive for the detection of disease sites, although there was no correlation between MET uptake and patient outcome. Kaste et al. [188] evaluated pediatric patients with lymphoma using 11C-methionine and compared it directly with FDG PET-CT for staging and follow-up. Whereas the results were fairly synchronous, 11C-methionine had the disadvantage of limited abdominal utility because of its uptake in normal structures. Furthermore, no advantage has been demonstrated over FDG-PET [189]. Rylova et al. [190] studied immune-PET imaging of CD30-positive lymphomas 90 using Zr-desferrioxamine-labeled CD30- specific AC-10 antibody in a preclinical model and suggested that this technique might be of value in Hodgkin lymphoma and other CD30- expressing tumors. Clinical trials have not been reported. Thus, at the present time, 18-FDG remains the preferred tracer for imaging patients with lymphoma. A. Gallamini et al. 134 7.8.2 uantitative Methods for PET Q Reading (SUV, MTV, TLG) 7.8.2.1 Semiquantitative Assessment Whereas the DS relies on the qualitative assessment of FDG uptake, Standardized Uptake Value (SUV), is the most widely used method of PET interpretation in HL, and more semiquantitative measures have been explored. The SUV is the most widely used parameter for quantitative analysis. It is readily available and well established in routine clinical work. Other investigators evaluated the SUVmax, which is the uptake in the single voxel exhibiting the highest tracer uptake. The SUVmax is easily available, has good interreader reproducibility, and is relatively unaffected by partial volume effects. SUVmean is the mean uptake in a larger user-defined region. Rossi et al. [191] conducted a retrospective analysis of 59 patients with HL who underwent PET after two cycles of anthracycline-based chemotherapy. The DS was compared with the ΔSUV comparing PET-0 with PET-2. A good response was considered a ΔSUV of at least 71%. Using the DS, 78% were considered to have a negative scan, seven of whom failed treatment for a NPV of 85%. The ΔSUVmax was greater than 71% in 83% of patients, six of whom failed treatment with a NPV of 88%. On the other hand, the PPV was superior for the ΔSUVmax at 70% vs. 46% using the DS. The ΔSUVmax reclassified 46% of the DS-positive patients as negative. Moreover, the ΔSUVmax was more accurate at predicting 4-year PFS 82% vs. 30%. Unfortunately, the ΔSUV is not yet ready to be adopted in general practice. This method of interpretation is not standardized, with different cutoffs in the various published studies. Further studies should clarify the value compared with standard interpretation. 7.8.2.2 Metabolic Tumor Volume A number of prognostic scoring systems are used by various investigators in patients with HL. Most of these include factors that are surrogates for tumor burden. The first attempt to approach the total tumor burden (TB) was made by Specht et al. [192] evaluating 290 patients with limited-stage HL. Data were supplied by the Danish National Hodgkin Study, with an index combining the tumor size of each involved region with the number of involved regions, sex, and histologic subtype to identify patients at a particularly poor risk following radiotherapy or chemoradiotherapy. Subsequently, other systems have been proposed using functional imaging. PET-CT affords the opportunity to provide a better assessment of tumor burden by measuring the total metabolic tumor volume (TMTV), which is related to both the tumor size and the activity of tumor and microenvironment cells. For these reasons, baseline TMTV has been suggested by several investigators to be a new risk factor to stratify early-stage patients. A high TMTV at baseline predicts a lower survival in early-stage HL [193, 194]. Using PET-CT, Cottereau et al. [60] evaluated the TMTV in 258 evaluable, high-risk, early-stage HL patients, treated on the H10 trial, 101 with favorable and 157 unfavorable disease. TMTV accurately predicted PFS and OS with 86% and 84% specificity, respectively. Indeed, TMTV identified 4 risk groups and was more accurate than baseline staging systems from the European Organization for the Research and Treatment of Cancer (EORTC), the German Hodgkin Study Group, the NCCN Network, and the Groupe d’Etude des Lymphomes de l’Adulte. The German Hodgkin Study Group evaluated 310 patients who underwent PET for staging and calculated MTV by four different methods [195] and found all predicted outcomes. Moskowitz [126] et al. reported a phase II, risk-adapted study in patients with relapsed or refractory HL. Transplant eligible patients received two or three cycles of brentuximab vedotin; those who became PET negative went on to ASCT. Those with residual disease received augmented ifosfamide, carboplatin, and etoposide (ICE) prior to ASCT. Three-year overall survival and event-free survival (EFS) were 95% and 82%, respectively. Factors predicting favorable outcome were low baseline metabolic tumor volume (<109.5 cm3) and relapsed disease, which was associated with a 100% likelihood of 3-year EFS. For patients who underwent ASCT, bMTV and pre-ASCT PET were independently prognos- 7 Functional Imaging in Hodgkin Lymphoma tic. The 3-year EFS for pre-ASCT PET-positive patients with low bMTV was 86%. Thus, bMTV improved the predictive power of pre-ASCT PET. In the future, consideration for ASCT should include such factors, to treat those patients most likely to benefit and to exclude those unlikely to do so. The use of interim PET remains controversial. It appears to permit escalation of treatment toward improved outcome in PET-positive patients HL, as well as a reduction in treatment for those whose scan is interpreted as negative. Although PET-2 is the most common time point for an interim study, other data suggest that PET as early as after the first cycle may be preferred. Hutchings et al. found a very high prognostic value of PET after one cycle of chemotherapy and a higher negative predictive value after one cycle than after two cycles of chemotherapy [66]. The authors concluded that PET after one cycle should be the preferred method for PET-response- adapted strategies designed to select patients candidate to a less intensive or a de-escalated treatment. Kostakoglu et al. has come to a similar conclusion [14]. However, earlier studies may be associated with a higher false positive rate [14]. Thus, at the present time, two cycles is the current standard. 7.9 General Recommendations for the Use of PET in HL Cheson et al. [9] recommended PET-CT as part of routine staging and restaging of patients with HL in the Lugano classification. A contrast- enhanced CT is not required unless measurement of a mass is critical to developing a treatment strategy. When used for initial staging, ample data support that a bone marrow aspirate and biopsy are no longer required. Interim PET may also be a valuable adjunct in Hodgkin lymphoma, as described above. A restaging study is best performed 6–8 weeks following the completion of standard induction therapy, with no contrast- enhanced CT indicated as whether there is evidence of persistent disease or not is what is critical. No additional scans are needed for sur- 135 veillance unless there is clinical evidence supporting disease recurrence. PET-CT provides important guidance for patients who relapse and are being considered candidates for intensive therapy with a stem cell transplant. Overall, PET-CT plays a major role in risk- adapted approaches as part of initial treatment, during interim evaluation, and in conjunction with other factors for patients being considered for various salvage strategies. References 1. Connors JM, Jurczak W, Straus DJ, Ansell SM, Kim WS, Gallamini A et al (2018) Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin’s lymphoma. N Engl J Med 378(4):331–344 2. Diehl V, Franklin J, Pfreundschuh M, Lathan B, Paulus U, Hasenclever D et al (2003) Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin's disease. N Engl J Med 348(24):2386–2395 3. Radford J, Illidge T, Counsell N, Hancock B, Pettengell R, Johnson P et al (2015) Results of a trial of PET-directed therapy for early-stage Hodgkin’s lymphoma. N Engl J Med 372(17):1598–1607 4. Johnson P, Federico M, Kirkwood A, Fossa A, Berkahn L, Carella A et al (2016) Adapted treatment guided by interim PET-CT scan in advanced Hodgkin’s lymphoma. N Engl J Med 374(25):2419–2429 5. Press OW, Li H, Schoder H, Straus DJ, Moskowitz CH, LeBlanc M et al (2016) US intergroup trial of response-adapted therapy for stage III to IV Hodgkin lymphoma using early interim Fluorodeoxyglucose- positron emission tomography imaging: southwest oncology group S0816. J Clin Oncol 34(17):2020–2027 6. Zinzani PL, Broccoli A, Gioia DM, Castagnoli A, Ciccone G, Evangelista A et al (2016) Interim positron emission tomography response-adapted therapy in advanced-stage Hodgkin lymphoma: final results of the phase II part of the HD0801 study. J Clin Oncol 34(12):1376–1385 7. Andre MPE, Girinsky T, Federico M, Reman O, Fortpied C, Gotti M et al (2017) Early positron emission tomography response-adapted treatment in stage I and II Hodgkin lymphoma: final results of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol 35(16):1786–1794 8. Cheson BD (2011) Role of functional imaging in the management of lymphoma. J Clin Oncol 29(14):1844–1854 9. Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E et al (2014) Recommendations for initial evaluation, staging, and response assessment A. Gallamini et al. 136 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 32(27):3059–3068 Barrington SF, Mikhaeel NG, Kostakoglu L, Meignan M, Hutchings M, Mueller SP et al (2014) Role of imaging in the staging and response assessment of lymphoma: consensus of the international conference on malignant lymphomas imaging working group. J Clin Oncol 32(27):3048–3058 Biggi A, Gallamini A, Chauvie S, Hutchings M, Kostakoglu L, Gregianin M et al (2013) International validation study for interim PET in ABVD-treated, advanced-stage Hodgkin lymphoma: interpretation criteria and concordance rate among reviewers. J Nucl Med 54(5):683–690 Gallamini A, Barrington SF, Biggi A, Chauvie S, Kostakoglu L, Gregianin M et al (2014) The predictive role of interim positron emission tomography for Hodgkin lymphoma treatment outcome is confirmed using the interpretation criteria of the Deauville five- point scale. Haematologica 99(6):1107–1113 Hutchings M, Loft A, Hansen M, Pedersen LM, Buhl T, Jurlander J et al (2006) FDG-PET after two cycles of chemotherapy predicts treatment failure and progression-free survival in Hodgkin lymphoma. Blood 107(1):52–59 Kostakoglu L, Goldsmith SJ, Leonard JP, Christos P, Furman RR, Atasever T et al (2006) FDG-PET after 1 cycle of therapy predicts outcome in diffuse large cell lymphoma and classic Hodgkin disease. Cancer 107(11):2678–2687 Gallamini A, Hutchings M, Rigacci L, Specht L, Merli F, Hansen M et al (2007) Early interim 2-[18F]fluoro2-deoxy-D-glucose positron emission tomography is prognostically superior to international prognostic score in advanced-stage Hodgkin’s lymphoma: a report from a joint Italian-Danish study. J Clin Oncol 25(24):3746–3752 Rigacci L, Puccini B, Zinzani PL, Biggi A, Castagnoli A, Merli F et al (2015) The prognostic value of positron emission tomography performed after two courses (INTERIM-PET) of standard therapy on treatment outcome in early stage Hodgkin lymphoma: a multicentric study by the fondazione italiana linfomi (FIL). Am J Hematol 90(6): 499–503 Gallamini A, Tarella C, Viviani S, Rossi A, Patti C, Mule A et al (2018) Early chemotherapy intensification with escalated BEACOPP in patients with advanced-stage Hodgkin lymphoma with a positive interim positron emission tomography/computed tomography scan after two ABVD cycles: long-term results of the GITIL/FIL HD 0607 trial. J Clin Oncol 36(5):454–462 Roemer MG, Advani RH, Ligon AH, Natkunam Y, Redd RA, Homer H et al (2016) PD-L1 and PD-L2 genetic alterations define classical Hodgkin lymphoma and predict outcome. J Clin Oncol 34(23):2690–2697 Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M et al (2015) PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med 372(4):311–319 20. Armand P, Engert A, Younes A, Fanale M, Santoro A, Zinzani PL et al (2018) Nivolumab for relapsed/ refractory classic Hodgkin lymphoma after failure of autologous hematopoietic cell transplantation: extended follow-up of the multicohort single- arm phase II CheckMate 205 trial. J Clin Oncol 36(14): 1428–1439 21. Chen R, Zinzani PL, Fanale MA, Armand P, Johnson NA, Brice P et al (2017) Phase II study of the efficacy and safety of Pembrolizumab for relapsed/ refractory classic Hodgkin lymphoma. J Clin Oncol 35(19):2125–2132 22. Engert A, Haverkamp H, Kobe C, Markova J, Renner C, Ho A et al (2012) Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced-stage Hodgkin’s lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial. Lancet 379(9828):1791–1799 23. Carbone PP, Kaplan HS, Musshoff K, Smithers DW, Tubiana M (1971) Report of the committee on Hodgkin’s disease staging classification. Cancer Res 31(11):1860–1861 24. Lister TA, Crowther D, Sutcliffe SB, Glatstein E, Canellos GP, Young RC et al (1989) Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin’s disease: Cotswolds meeting. J Clin Oncol 7(11):1630–1636 25. Glatstein E, Guernsey JM, Rosenberg SA, Kaplan HS (1969) The value of laparotomy and splenectomy in the staging of Hodgkin’s disease. Cancer 24(4):709–718 26. Castellino RA, Hoppe RT, Blank N, Young SW, Neumann C, Rosenberg SA et al (1984) Computed tomography, lymphography, and staging laparotomy: correlations in initial staging of Hodgkin disease. AJR Am J Roentgenol 143(1):37–41 27. DeVita VT Jr, Simon RM, Hubbard SM, Young RC, Berard CW, Moxley JH III et al (1980) Curability of advanced Hodgkin’s disease with chemotherapy. Long-term follow-up of MOPP-treated patients at the National Cancer Institute. Ann Intern Med 92(5):587–595 28. Gospodarowicz MK, O'Sullivan B, Koh ES (2006) Prognostic factors: principles and applications. In: Gospodarowicz MK, O’Sullivan B, Sobin LH (eds) Prognostic factors in cancer, 3rd edn. Wiley-Liss, Hoboken, NJ, pp 23–28 29. Diehl V, Stein H, Hummel M, Zollinger R, Connors JM (2003) Hodgkin’s lymphoma: biology and treatment strategies for primary, refractory, and relapsed disease. Hematology Am Soc Hematol Educ Program 2003:225–247 30. Hutchings M, Loft A, Hansen M, Pedersen LM, Berthelsen AK, Keiding S et al (2006) Position emission tomography with or without computed tomography in the primary staging of Hodgkin’s lymphoma. Haematologica 91(4):482–489 31. El Galaly TC, d'Amore F, Mylam KJ, Nully Brown P, Bgsted M, Bukh A et al (2012) Routine bone marrow biopsy has little or no therapeutic consequence for positron emission tomography/computed 7 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. Functional Imaging in Hodgkin Lymphoma tomography- staged treatment-naive patients with Hodgkin lymphoma. J Clin Oncol 30(36):4508–4514 Alzahrani M, El-Galaly TC, Hutchings M, Hansen JW, Loft A, Johnsen HE et al (2016) The value of routine bone marrow biopsy in patients with diffuse large B-cell lymphoma staged with PET/CT: a DanishCanadian study. Ann Oncol 27(6):1095–1099 Thompson CJ (2002) Instrumentation. In: Wahl RL (ed) Principles and practice of positron emission tomography. Lippincott Williams & Wilkins, Philadelphia, PA, pp 48–64 Finn RD, Schlyer DJ (2002) Production of radionuclides for PET. In: Wahl RL (ed) Principles and practice of positron emission tomography. Lippincott Williams & Wilkins, Philadelphia, PA, pp 1–15 Fowler JS, Ding Y (2002) Chemistry. In: Wahl RL (ed) Principles and practice of positron emission tomography. Lippincott Williams & Wilkins, Philadelphia, PA, pp 16–47 Ell PJ, von Schulthess GKPET (2002) CT: a new road map. Eur J Nucl Med Mol Imaging 29(6):719–720 Warburg O (1926) Über den Stoffwechsel der Tumoren: arbeiten aus dem Kaiser Wilhelm-Institut für Biologie, Berlin-Dahlem. Springer, Berlin Au KK, Liong E, Li JY, Li PS, Liew CC, Kwok TT et al (1997) Increases in mRNA levels of glucose transporters types 1 and 3 in Ehrlich ascites tumor cells during tumor development. J Cell Biochem 67(1):131–135 Yamamoto T, Seino Y, Fukumoto H, Koh G, Yano H, Inagaki N et al (1990) Over-expression of facilitative glucose transporter genes in human cancer. Biochem Biophys Res Commun 170(1):223–230 Brown RS, Wahl RL (1993) Overexpression of Glut-1 glucose transporter in human breast cancer. An immunohistochemical study. Cancer 72(10):2979–2985 Aloj L, Caraco C, Jagoda E, Eckelman WC, Neumann RD (1999) Glut-1 and hexokinase expression: relationship with 2-fluoro-2-deoxy-D-glucose uptake in A431 and T47D cells in culture. Cancer Res 59(18):4709–4714 Higashi K, Clavo AC, Wahl RL (1993) Does FDG uptake measure proliferative activity of human cancer cells? In vitro comparison with DNA flow cytometry and tritiated thymidine uptake. J Nucl Med 34(3):414–419 Brown RS, Leung JY, Fisher SJ, Frey KA, Ethier SP, Wahl RL (1996) Intratumoral distribution of tritiated- FDG in breast carcinoma: correlation between Glut-1 expression and FDG uptake. J Nucl Med 37(6):1042–1047 Wahl RL, Henry CA, Ethier SP (1992) Serum glucose: effects on tumor and normal tissue accumulation of 2-[F-18]-fluoro-2-deoxy-D-glucose in rodents with mammary carcinoma. Radiology 183(3):643–647 Clavo AC, Brown RS, Wahl RL (1995) Fluorodeoxyglucose uptake in human cancer cell lines is increased by hypoxia. J Nucl Med 36(9):1625–1632 Kubota R, Yamada S, Kubota K, Ishiwata K, Tamahashi N, Ido T (1992) Intratumoral distribution of fluorine-18-fluorodeoxyglucose in vivo: high 137 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. accumulation in macrophages and granulation tissues studied by microautoradiography. J Nucl Med 33(11):1972–1980 Brown RS, Leung JY, Fisher SJ, Frey KA, Ethier SP, Wahl RL (1995) Intratumoral distribution of tritiated fluorodeoxyglucose in breast carcinoma: I. Are inflammatory cells important? J Nucl Med 36(10):1854–1861 Higashi K, Clavo AC, Wahl RL (1993) In vitro assessment of 2-fluoro-2-deoxy-D-glucose, L-methionine and thymidine as agents to monitor the early response of a human adenocarcinoma cell line to radiotherapy. J Nucl Med 34(5):773–779 Spaepen K, Stroobants S, Dupont P, Bormans G, Balzarini J, Verhoef G et al (2003) [(18)F]FDG PET monitoring of tumour response to chemotherapy: does [(18)F]FDG uptake correlate with the viable tumour cell fraction? Eur J Nucl Med Mol Imaging 30(5):682–688 Hutchings M, Loft A, El-Galaly TC (2016) PET/ CT for Hodgkin lymphoma staging. In: Gallamini A (ed) PET scan in Hodgkin lymphoma. Springer, Heidelberg, pp 1–13 Bednaruk-Mlynski E, Pienkowska JF, Skorzak AF, Malkowski BF, Kulikowski WF, Subocz EF, Dzietczenia J et al (2015) Comparison of positron emission tomography/computed tomography with classical contrast-enhanced computed tomography in the initial staging of Hodgkin lymphoma. Leuk Lymphoma 56(2):377–382 Barrington SF, Kirkwood AA, Franceschetto A, Fulham MJ, Roberts TH, Almquist H et al (2016) PET-CT for staging and early response: results from the response-adapted therapy in advanced Hodgkin lymphoma study. Blood 127(12):1531–1538 Weiler-Sagie M, Kagna O, Dann EJ, Ben-Barak A, Israel O (2014) Characterizing bone marrow involvement in Hodgkin’s lymphoma by FDG-PET/CT. Eur J Nucl Med Mol Imaging 41(6):1133–1140 Zwarthoed C, El-Galaly TC, Canepari M, Ouvrier MJ, Viotti J, Ettaiche M et al (2017) Prognostic value of bone marrow tracer uptake pattern in baseline PET scans in Hodgkin lymphoma: results from an international collaborative study. J Nucl Med 58(8):1249–1254 Levis A, Pietrasanta D, Godio L, Vitolo U, Ciravegna G, Di Vito F et al (2004) A large-scale study of bone marrow involvement in patients with Hodgkin’s lymphoma. Clin Lymphoma 5(1):50–55 Brunning RD, Bloomfield CD, McKenna RW, Peterson LA (1975) Bilateral trephine bone marrow biopsies in lymphoma and other neoplastic diseases. Ann Intern Med 82(3):365–366 Voltin CA, Goergen H, Baues C, Fuchs M, Mettler J, Kreissl S et al (2018) Value of bone marrow biopsy in Hodgkin lymphoma patients staged by FDG PET: results from the German Hodgkin study group trials HD16, HD17, and HD18. Ann Oncol 29(9):1926–1931 Purz S, Mauz-Korholz C, Korholz D, Hasenclever D, Krausse A, Sorge I et al (2011) [18F] A. Gallamini et al. 138 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. Fluorodeoxyglucose positron emission tomography for detection of bone marrow involvement in children and adolescents with Hodgkin’s lymphoma. J Clin Oncol 29(26):3523–3528 Ferme C, Eghbali H, Meerwaldt JH, Rieux C, Bosq J, Berger F et al (2007) Chemotherapy plus involved- field radiation in early-stage Hodgkin’s disease. N Engl J Med 357(19):1916–1927 Cottereau AS, Versari A, Loft A, Casasnovas O, Bellei M, Ricci R et al (2018) Prognostic value of baseline metabolic tumor volume in early-stage Hodgkin lymphoma in the standard arm of the H10 trial. Blood 131(13):1456–1463 Kostakoglu L, Chauvie S (2018) Metabolic tumor volume metrics in lymphoma. Semin Nucl Med 48(1):50–66 Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92(3):205–216 Radford JA, Cowan RA, Flanagan M, Dunn G, Crowther D, Johnson RJ et al (1988) The significance of residual mediastinal abnormality on the chest radiograph following treatment for Hodgkin’s disease. J Clin Oncol 6(6):940–946 Surbone A, Longo DL, DeVita VT Jr, Ihde DC, Duffey PL, Jaffe ES et al (1988) Residual abdominal masses in aggressive non-Hodgkin’s lymphoma after combination chemotherapy: significance and management. J Clin Oncol 6(12):1832–1837 Naumann R, Vaic A, Beuthien-Baumann B, Bredow J, Kropp J, Kittner T et al (2001) Prognostic value of positron emission tomography in the evaluation of post-treatment residual mass in patients with Hodgkin's disease and non-Hodgkin’s lymphoma. Br J Haematol 115(4):793–800 Hutchings M, Kostakoglu L, Zaucha JM, Malkowski B, Biggi A, Danielewicz I et al (2014) In vivo treatment sensitivity testing with positron emission tomography/computed tomography after one cycle of chemotherapy for Hodgkin lymphoma. J Clin Oncol 32(25):2705–2711 Zaucha JM, Malkowski B, Chauvie S, Subocz E, Tajer J, Kulikowski W et al (2017) The predictive role of interim PET after the first chemotherapy cycle and sequential evaluation of response to ABVD in Hodgkin’s lymphoma patients-the polish lymphoma research group (PLRG) observational study. Ann Oncol 28(12):3051–3057 Cerci JJ, Pracchia LF, Linardi CC, Pitella FA, Delbeke D, Izaki M et al (2010) 18F-FDG PET after 2 cycles of ABVD predicts event-free survival in early and advanced Hodgkin lymphoma. J Nucl Med 51(9):1337–1343 Zinzani P, Rigacci L, Stefoni V, Broccoli A, Puccini B, Castagnoli A et al (2012) Early interim 18FFDG PET in Hodgkin’s lymphoma: evaluation on 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 304 patients. Eur J Nucl Med Mol Imaging 39(1): 4–12 Terasawa T, Lau J, Bardet S, Couturier O, Hotta T, Hutchings M et al (2009) Fluorine-18- fluorodeoxyglucose positron emission tomography for interim response assessment of advanced-stage Hodgkin’s lymphoma and diffuse large B-cell lymphoma: a systematic review. J Clin Oncol 27(11):1906–1914 Maynard J, Emmas SA, Ble FX, Barjat H, Lawrie E, Hancox U et al (2016) The use of (18) F-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) as a pathway-specific biomarker with AZD8186, a PI3Kbeta/delta inhibitor. EJNMMI Res 6(1):62 Simontacchi G, Filippi AR, Ciammella P, Buglione M, Saieva C, Magrini SM et al (2015) Interim PET after two ABVD cycles in early-stage Hodgkin lymphoma: outcomes following the continuation of chemotherapy plus radiotherapy. Int J Radiat Oncol Biol Phys 92(5):1077–1083 Evens AM, Kostakoglu L (2014) The role of FDG- PET in defining prognosis of Hodgkin lymphoma for early-stage disease. Blood 124(23):3356–3364 Sher DJ, Mauch PM, Van Den Abbeele A, LaCasce AS, Czerminski J, Ng AK (2009) Prognostic significance of mid- and post-ABVD PET imaging in Hodgkin’s lymphoma: the importance of involved- field radiotherapy. Ann Oncol 20(11):1848–1853 Engles JM, Quarless SA, Mambo E, Ishimori T, Cho SY, Wahl RL (2006) Stunning and its effect on 3H-FDG uptake and key gene expression in breast cancer cells undergoing chemotherapy. J Nucl Med 47(4):603–608 Kasamon YL, Jones RJ, Wahl RL (2007) Integrating PET and PET/CT into the risk-adapted therapy of lymphoma. J Nucl Med 48(Suppl 1):19S–27S Zijlstra JM, Lindauer-van der Werf G, Hoekstra OS, Hooft L, Riphagen II, Huijgens PC (2006) 18F-fluorodeoxyglucose positron emission tomography for post-treatment evaluation of malignant lymphoma: a systematic review. Haematologica 91(4):522–529 Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ et al (2007) Revised response criteria for malignant lymphoma. J Clin Oncol 25(5):579–586 Meignan M, Gallamini A, Meignan M, Gallamini A, Haioun C (2009) Report on the first international workshop on interim-PET scan in lymphoma. Leuk Lymphoma 50(8):1257–1260 Barnes JA, LaCasce AS, Zukotynski K, Israel D, Feng Y, Neuberg D et al (2011) End-of-treatment but not interim PET scan predicts outcome in nonbulky limited-stage Hodgkin’s lymphoma. Ann Oncol 22(4):910–915 Fallanca F, Alongi P, Incerti E, Gianolli L, Picchio M, Kayani I et al (2016) Diagnostic accuracy of FDG PET/CT for clinical evaluation at the end of treatment of HL and NHL: a comparison of the Deauville criteria (DC) and the international harmonization proj- 7 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. Functional Imaging in Hodgkin Lymphoma ect criteria (IHPC). Eur J Nucl Med Mol Imaging 43(10):1837–1848 Jerusalem G, Beguin Y, Fassotte MF, Najjar F, Paulus P, Rigo P et al (1999) Whole-body positron emission tomography using 18F-fluorodeoxyglucose for posttreatment evaluation in Hodgkin's disease and non-Hodgkin's lymphoma has higher diagnostic and prognostic value than classical computed tomography scan imaging. Blood 94(2):429–433 Terasawa T, Nihashi T, Hotta T, Nagai H (2008) 18F- FDG PET for posttherapy assessment of Hodgkin’s disease and aggressive non-Hodgkin's lymphoma: a systematic review. J Nucl Med 49(1):13–21 Savage KJ, Connors JM, Villa DR, Hapgood G, Gerrie AS, Shenkier TN et al (2015) Advanced-stage classical Hodgkin lymphoma patients with a negative PET-scan following treatment with ABVD have excellent outcomes without the need for consolidative radiotherapy regardless of disease bulk at presentation. Blood 126(23):579 Picardi M, De Renzo A, Pane F, Nicolai E, Pacelli R, Salvatore M et al (2007) Randomized comparison of consolidation radiation versus observation in bulky Hodgkin’s lymphoma with post-chemotherapy negative positron emission tomography scans. Leuk Lymphoma 48(9):1721–1727 Hutchings M, Mikhaeel NG, Fields PA, Nunan T, Timothy AR (2005) Prognostic value of interim FDG-PET after two or three cycles of chemotherapy in Hodgkin lymphoma. Ann Oncol 16(7): 1160–1168 Gallamini A, Fiore F, Sorasio R, Meignan M (2009) Interim positron emission tomography scan in Hodgkin lymphoma: definitions, interpretation rules, and clinical validation. Leuk Lymphoma 50(11):1761–1764 Hoppe RT, Advani RH, Ai WZ, Ambinder RF, Aoun P, Armand P et al (2018) NCCN guidelines insights: Hodgkin lymphoma, version 1. J Natl Compr Canc Netw 16(3):245–254 Eichenauer DA, Aleman BMP, Andre M, Federico M, Hutchings M, Illidge T et al (2018) Hodgkin lymphoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 29:iv19 Follows GA, Ardeshna KM, Barrington SF, Culligan DJ, Hoskin PJ, Linch D et al (2014) Guidelines for the first line management of classical Hodgkin lymphoma. Br J Haematol 166(1):34–49 Barrington SF, Qian W, Somer EJ, Franceschetto A, Bagni B, Brun E et al (2010) Concordance between four European centres of PET reporting criteria designed for use in multicentre trials in Hodgkin lymphoma. Eur J Nucl Med Mol Imaging 37(10):1824–1833 Hasenclever D, Kurch LF, Mauz-Korholz CF, Elsner AF, Georgi TF, Wallace HF et al (2014) qPET – a quantitative extension of the Deauville scale to assess response in interim FDG-PET scans in lymphoma. Eur J Nucl Med Mol Imaging 41(7): 1301–1308 139 93. Canellos GP (1988) Residual mass in lymphoma may not be residual disease. J Clin Oncol 6(6): 931–933 94. van BK, Kelta M, Bahaguna P (2001) Primary mediastinal B-cell lymphoma: a review of pathology and management. J Clin Oncol 19(6):1855–1864 95. Savage KJ, Monti S, Kutok JL, Cattoretti G, Neuberg D, De LL et al (2003) The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma. Blood 102(12):3871–3879 96. Martelli M, Ceriani L, Zucca E, Zinzani PL, Ferreri AJ, Vitolo U et al (2014) [18F]fluorodeoxyglucose positron emission tomography predicts survival after chemoimmunotherapy for primary mediastinal large B-cell lymphoma: results of the international extranodal lymphoma study group IELSG-26 study. J Clin Oncol 32(17):1769–1775 97. Melani C, Advani R, Roschewski M, Walters KM, Chen CC, Baratto L et al (2018) End-of-treatment and serial PET imaging in primary mediastinal B-cell lymphoma following dose-adjusted EPOCH-R: a paradigm shift in clinical decision making. Haematologica 103(8):1337–1344 98. Pinnix CC, Ng AK, Dabaja BS, Milgrom SA, Gunther JR, Fuller CD et al (2018) Positron emission tomography-computed tomography predictors of progression after DA-R-EPOCH for PMBCL. Blood Adv 2(11):1334–1343 99. Barrington SF, Kluge R (2017) FDG PET for therapy monitoring in Hodgkin and non-Hodgkin lymphomas. Eur J Nucl Med Mol Imaging 44(Suppl 1):97–110 100. Robert C, Schachter JF, Long GV, Arance A, Arance AF, Grob JJ, Mortier L, Mortier LF et al (2015) Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 372(26):2521–2532 101. Herbst RS, Baas P, Kim DW, Felip E, Perez- Gracia JL, Han JY et al (2016) Pembrolizumab versus docetaxel for previously treated, PD-L1- positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387(10027):1540–1550 102. Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S et al (2015) Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 373(19):1803–1813 103. Armand P, Shipp MA, Ribrag V, Michot JM, Zinzani PL, Kuruvilla J et al (2016) Programmed death-1 blockade with pembrolizumab in patients with classical Hodgkin lymphoma after brentuximab vedotin failure. J Clin Oncol 34(31): 3733–3739 104. Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12(4):252–264 105. Cheson BD, Ansell S, Schwartz L, Gordon LI, Advani R, Jacene HA et al (2016) Refinement of the Lugano classification lymphoma response crite- A. Gallamini et al. 140 106. 107. 108. 109. 110. 111. 112. 113. 114. 115. 116. ria in the era of immunomodulatory therapy. Blood 128(21):2489 Girinsky T, Pichenot C, Beaudre A, Ghalibafian M, Lefkopoulos D (2006) Is intensity-modulated radiotherapy better than conventional radiation treatment and three-dimensional conformal radiotherapy for mediastinal masses in patients with Hodgkin’s disease, and is there a role for beam orientation optimization and dose constraints assigned to virtual volumes? Int J Radiat Oncol Biol Phys 64(1):218–226 Girinsky T, van der Maazen R, Specht L, Aleman B, Poortmans P, Lievens Y et al (2006) Involved-node radiotherapy (INRT) in patients with early Hodgkin lymphoma: concepts and guidelines. Radiother Oncol 79(3):270–277 Specht L, Gray RG, Clarke MJ, Peto R (1998) Influence of more extensive radiotherapy and adjuvant chemotherapy on long-term outcome of early-stage Hodgkin's disease: a meta-analysis of 23 randomized trials involving 3,888 patients. International Hodgkin's disease collaborative group. J Clin Oncol 16(3):830–843 Yahalom J (2005) Transformation in the use of radiation therapy of Hodgkin lymphoma: new concepts and indications lead to modern field design and are assisted by PET imaging and intensity modulated radiation therapy (IMRT). Eur J Haematol Suppl 66:90–97 Gregoire V (2004) Is there any future in radiotherapy planning without the use of PET: unraveling the myth. Radiother Oncol 73(3):261–263 Berthelsen AK, Dobbs J, Kjellén E, Landberg T, Möller T, Nilsson P et al (2007) What’s new in target volume definitions for radiologists in ICRU report 71? How can the ICRU volume definitions be integrated in clinical practice? Cancer Imaging 7(1):104–116 Jarritt PH, Carson KJ, Hounsell AR, Visvikis D (2006) The role of PET/CT scanning in radiotherapy planning. Br J Radiol 79(1):S27–S35 Specht L, Yahalom J, Illidge T, Berthelsen AK, Constine LS, Eich HT et al (2014) Modern radiation therapy for Hodgkin lymphoma: field and dose guidelines from the international lymphoma radiation oncology group (ILROG). Int J Radiat Oncol Biol Phys 89(4):854–862 Specht L (2007) 2-[18F]fluoro-2-deoxyglucose positron-emission tomography in staging, response evaluation, and treatment planning of lymphomas. Semin Radiat Oncol 17(3):190–197 van Baardwijk A, Baumert BG, Bosmans G, van Kroonenburgh M, Stroobants S, Gregoire V et al (2006) The current status of FDG-PET in tumour volume definition in radiotherapy treatment planning. Cancer Treat Rev 32(4):245–260 Dizendorf EV, Baumert BG, von Schulthess GK, Lutolf UM, Steinert HC (2003) Impact of whole-body 18F-FDG PET on staging and managing patients for radiation therapy. J Nucl Med 44(1):24–29 117. Lee YK, Cook G, Flower MA, Rowbottom C, Shahidi M, Sharma B et al (2004) Addition of 18F-FDG-PET scans to radiotherapy planning of thoracic lymphoma. Radiother Oncol 73(3): 277–283 118. Hutchings M, Loft A, Hansen M, Berthelsen AK, Specht L (2007) Clinical impact of FDG-PET/CT in the planning of radiotherapy for early-stage Hodgkin lymphoma. Eur J Haematol 78(3):206–212 119. Girinsky T, Ghalibafian M, Bonniaud G, Bayla A, Magne N, Ferreira I et al (2007) Is FDG-PET scan in patients with early stage Hodgkin lymphoma of any value in the implementation of the involved-node radiotherapy concept and dose painting? Radiother Oncol 85(2):178–186 120. Josting A, Muller H, Borchmann P, Baars JW, Metzner B, Dohner H et al (2010) Dose intensity of chemotherapy in patients with relapsed Hodgkin’s lymphoma. J Clin Oncol 28(34):5074–5080 121. Brockelmann PJ, Muller H, Casasnovas O, Hutchings M, von TB, Jurgens M et al (2017) Risk factors and a prognostic score for survival after autologous stem-cell transplantation for relapsed or refractory Hodgkin lymphoma. Ann Oncol 28(6):1352–1358 122. Moskowitz CH, Matasar MJ, Zelenetz AD, Nimer SD, Gerecitano J, Hamlin P et al (2012) Normalization of pre-ASCT, FDG-PET imaging with second-line, non-cross-resistant, chemotherapy programs improves event-free survival in patients with Hodgkin lymphoma. Blood 119(7): 1665–1670 123. Gentzler RD, Evens AM, Rademaker AW, Weitner BB, Mittal BB, Dillehay GL et al (2014) F-18 FDG- PET predicts outcomes for patients receiving total lymphoid irradiation and autologous blood stem-cell transplantation for relapsed and refractory Hodgkin lymphoma. Br J Haematol 165(6):793–800 124. Devillier R, Coso D, Castagna L, Brenot R, Anastasia A, Chiti A et al (2012) positron emission tomography response at the time of autologous stem cell transplantation predicts outcome of patients with relapsed and/or refractory Hodgkin's lymphoma responding to prior salvage therapy. Haematologica 97(7):1073–1079 125. Poulou LS, Thanos L, Ziakas PD (2010) Unifying the predictive value of pretransplant FDG PET in patients with lymphoma: a review and meta-analysis of published trials. Eur J Nucl Med Mol Imaging 37(1):156–162 126. Moskowitz AJ, Schoder H, Gavane S, Thoren KL, Fleisher M, Yahalom J et al (2017) Prognostic significance of baseline metabolic tumor volume in relapsed and refractory Hodgkin lymphoma. Blood 130(20):2196–2203 127. Gallamini A (2017) Relapsed/refractory HL: FDG- PET is the trump card. Blood 130(20):2154–2155 128. Armitage JO, Loberiza FR (2006) Is there a place for routine imaging for patients in complete remission from aggressive lymphoma? Ann Oncol 17(6):883–884 129. Radford JA, Eardley A, Woodman C, Crowther D (1997) Follow up policy after treatment for 7 Functional Imaging in Hodgkin Lymphoma 130. 131. 132. 133. 134. 135. 136. 137. 138. 139. 140. Hodgkin’s disease: too many clinic visits and routine tests? A review of hospital records. BMJ 314(7077):343–346 Gallamini A, Kostakoglu L (2012) Positron emission tomography/computed tomography surveillance in patients with lymphoma: a fox hunt? Haematologica 97(6):797–799 Petrausch U, Samaras P, Veit-Haibach P, Tschopp A, Soyka JD, Knuth A et al (2010) Hodgkin’s lymphoma in remission after first-line therapy: which patients need FDG-PET/CT for follow-up? Ann Oncol 21(5):1053–1057 Zinzani PL, Stefoni V, Tani M, Fanti S, Musuraca G, Castellucci P et al (2009) Role of [18F]fluorodeoxyglucose positron emission tomography scan in the follow-up of lymphoma. J Clin Oncol 27(11):1781–1787 Jerusalem G, Beguin Y, Fassotte MF, Belhocine T, Hustinx R, Rigo P et al (2003) Early detection of relapse by whole-body positron emission tomography in the follow-up of patients with Hodgkin's disease. Ann Oncol 14(1):123–130 El Galaly TC, Mylam KJ, Brown P, Specht L, Christiansen I, Munksgaard L et al (2012) Positron emission tomography/computed tomography surveillance in patients with Hodgkin lymphoma in first remission has a low positive predictive value and high costs. Haematologica 97(6):931–936 Aleman BM, van den Belt-Dusebout AW, Klokman WJ, Van’t Veer MB, Bartelink H, van Leeuwen FE (2003) Long-term cause-specific mortality of patients treated for Hodgkin's disease. J Clin Oncol 21(18):3431–3439 Raemaekers JM, Andre MP, Federico M, Girinsky T, Oumedaly R, Brusamolino E et al (2014) Omitting radiotherapy in early positron emission tomography- negative stage I/II Hodgkin lymphoma is associated with an increased risk of early relapse: clinical results of the preplanned interim analysis of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol 32(12):1188–1194 Fuchs M, Goergen H, Kobe C, Kuhnert G, Lohri A, Greil R et al (2019) Positron Emission Tomographyguided treatment in early-stage favorable Hodgkin lymphoma: final results of the international, randomized phase III HD16 trial by the German Hodgkin Study Group. J Clin Oncol 37(31):2835–2845 Engert A, Diehl V, Franklin J, Lohri A, Dorken B, Ludwig WD et al (2009) Escalated-dose BEACOPP in the treatment of patients with advanced-stage Hodgkin's lymphoma: 10 years of follow-up of the GHSG HD9 study. J Clin Oncol 27(27):4548–4554 Trotman J (2017) Foss+Ñ a, Federico M, Stevens L, Kirkwood a, Clifton-Hadley L, et al. Response- adjusted therapy for advanced Hodgkin lymphoma (rathl) trial: longer follow up confirms efficacy of de-escalation after a negative interim PET scan (CRUK/07/033). Hematol Oncol 35(S2):65–67 Borchmann P, Goergen H, Kobe C, Lohri A, Greil R, Eichenauer DA et al (2018) PET-guided treatment in patients with advanced-stage Hodgkin’s lymphoma 141 141. 142. 143. 144. 145. 146. 147. 148. 149. 150. (HD18): final results of an open-label, international, randomised phase 3 trial by the German Hodgkin study group. Lancet 390(10114):2790–2802 Borchmann P, Goergen H, Kobe C, Lohri A, Greil R, Eichenauer DA et al (2017) Early interim PET in patients with advanced-stage Hodgkin’s lymphoma treated within the phase 3 GHSG HD18 study. Blood 130(Suppl 1):737 Casasnovas RO, Bouabdallah R, Brice P, Lazarovici J, Ghesquieres H, Stamatoullas A et al (2019) PET- adapted treatment for newly diagnosed advanced Hodgkin lymphoma (AHL2011): a randomised, multicentre, non-inferiority, phase 3 study. Lancet Oncol 20(2):202–215 Kobe C, Dietlein M, Franklin J, Markova J, Lohri A, Amthauer H et al (2008) Positron emission tomography has a high negative predictive value for progression or early relapse for patients with residual disease after first-line chemotherapy in advanced-stage Hodgkin lymphoma. Blood 112(10):3989–3994 Mocikova H, Pytlik R, Markova J, Steinerova K, Kral Z, Belada D et al (2011) Pre-transplant positron emission tomography in relapsed Hodgkin lymphoma patients. Leuk Lymphoma 52:1668 Smeltzer JP, Cashen AF, Zhang Q, Homb A, Dehdashti F, Abboud CN et al (2011) Prognostic significance of FDG-PET in relapsed or refractory classical Hodgkin lymphoma treated with standard salvage chemotherapy and autologous stem cell transplantation. Biol Blood Marrow Transplant 17(11):1646–1652 Moskowitz AJ, Yahalom J, Kewalramani T, Maragulia JC, Vanak JM, Zelenetz AD et al (2010) Pretransplantation functional imaging predicts outcome following autologous stem cell transplantation for relapsed and refractory Hodgkin lymphoma. Blood 116(23):4934–4937 Moskowitz AJ, Schoder H, Yahalom J, McCall SJ, Fox SY, Gerecitano J et al (2015) PET-adapted sequential salvage therapy with brentuximab vedotin followed by augmented ifosfamide, carboplatin, and etoposide for patients with relapsed and refractory Hodgkin's lymphoma: a non-randomised, open- label, single-centre, phase 2 study. Lancet Oncol 16(3):284–292 Reyal Y, Kayani I, Bloor AJC, Fox CP, Chakraverty R, Sjursen AM et al (2016) Impact of pretransplantation 18F-fluorodeoxyglucose-positron emission tomography on survival outcomes after T cell depleted allogeneic transplantation for Hodgkin lymphoma. Biol Blood Marrow Transplant 22(7):1234–1241 Marani C, Raiola AM, Morbelli S, Dominietto A, Ferrarazzo G, Avenoso D et al (2018) Haploientical transplants with post-transplant cyclophosphamide for relapsed or refractory Hodgkin lymphoma: the role of comorbidity index and Pretransplant positron emission tomography. Biol Blood Marrow Transplant 24(12):2501–2508 Dodero A, Crocchiolo R, Patriarca F, Miceli R, Castagna L, Ciceri F et al (2010) Pretransplantation A. Gallamini et al. 142 151. 152. 153. 154. 155. 156. 157. 158. 159. 160. [18-F]fluorodeoxyglucose positron emission tomography scan predicts outcome in patients with recurrent Hodgkin lymphoma or aggressive non-Hodgkin lymphoma undergoing reduced-intensity conditioning followed by allogeneic stem cell transplantation. Cancer 116(21):5001–5011 Lambert JR, Bomanji JB, Peggs KS, Thomson KJ, Chakraverty RK, Fielding AK et al (2010) Prognostic role of PET scanning before and after reduced-intensity allogeneic stem cell transplantation for lymphoma. Blood 115(14):2763–2768 Hart DP, Avivi I, Thomson KJ, Peggs KS, Morris EC, Goldstone AH et al (2005) Use of 18F-FDG positron emission tomography following allogeneic transplantation to guide adoptive immunotherapy with donor lymphocyte infusions. Br J Haematol 128(6):824–829 Juweid ME, Wiseman GA, Vose JM, Ritchie JM, Menda Y, Wooldridge JE et al (2005) Response assessment of aggressive non-Hodgkin's lymphoma by integrated international workshop criteria and fluorine-18-fluorodeoxyglucose positron emission tomography. J Clin Oncol 23(21):4652–4661 Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, Connors JM et al (1999) Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working Group. J Clin Oncol 17(4):1244 Trotman J, Luminari S, Boussetta S, Versari A, Dupuis J, Tychyj C et al (2014) Prognostic value of PET-CT after first-line therapy in patients with follicular lymphoma: a pooled analysis of central scan review in three multicentre studies. Lancet Haematol 1(1):e17–e27 Puccini B, Nassi L, Minoia C, Volpetti S, Ciancia R, Riccomagno PC et al (2017) Role of bone marrow biopsy in staging of patients with classical Hodgkin's lymphoma undergoing positron emission tomography/computed tomography. Ann Hematol 96(7):1147–1153 Eve HE, Rule SA (2010) Lenalidomide-induced tumour flare reaction in mantle cell lymphoma. Br J Haematol 151(4):410–412 Corazzelli G, De FR, Capobianco G, Frigeri F, De R et al (2010) Tumor flare reactions and response to lenalidomide in patients with refractory classic Hodgkin lymphoma. Am J Hematol 85(1): 87–90 Andritsos LA, Johnson AJ, Lozanski G, Blum W, Kefauver C, Awan F et al (2008) Higher doses of lenalidomide are associated with unacceptable toxicity including life-threatening tumor flare in patients with chronic lymphocytic leukemia. J Clin Oncol 26(15):2519–2525 Chanan-Khan A, Miller KC, Musial L, Lawrence D, Padmanabhan S, Takeshita K et al (2006) Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study. J Clin Oncol 24(34):5343–5349 161. Han HS, Escalon MP, Hsiao B, Serafini A, Lossos IS (2009) High incidence of false-positive PET scans in patients with aggressive non-Hodgkin's lymphoma treated with rituximab-containing regimens. Ann Oncol 20(2):309–318 162. Skoura E, Ardeshna K, Halsey R, Wan S, Kayani I (2016) False-positive 18F-FDG PET/CT imaging: dramatic “flare response” after rituximab administration. Clin Nucl Med 41(3):e171–e172 163. Pro B, Advani R, Brice P, Bartlett NL, Rosenblatt JD, Illidge T et al (2012) Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol 30(18):2190–2196 164. Gopal AK, Schuster SJ, Fowler NH, Trotman J, Hess G, Hou JZ et al (2018) Ibrutinib as treatment for patients with relapsed/refractory follicular lymphoma: results from the open-label, multicenter, phase II DAWN study. J Clin Oncol 36(23):2405–2412 165. Brown JR, Byrd JC, Coutre SE, Benson DM, Flinn IW, Wagner-Johnston ND et al (2014) Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110delta, for relapsed/refractory chronic lymphocytic leukemia. Blood 123(22):3390–3397 166. Kurtz DM, Green MR, Bratman SV, Scherer F, Liu CL, Kunder CA et al (2015) Noninvasive monitoring of diffuse large B-cell lymphoma by immunoglobulin high-throughput sequencing. Blood 125(24):3679–3687 167. van Eijndhoven MA, Zijlstra JM, Groenewegen NJ, Drees EE et al (2016) Plasma vesicle miRNAs for therapy response monitoring in Hodgkin lymphoma patients. JCI Insight 1(19):e89631 168. Spina V, Bruscaggin A, Cuccaro A, Martini M, Di TM, Forestieri G et al (2018) Circulating tumor DNA reveals genetics, clonal evolution, and residual disease in classical Hodgkin lymphoma. Blood 131(22):2413–2425 169. Cuccaro A, Annunziata S, Cupelli E, Martini M, Calcagni ML, Rufini V et al (2016) CD68+ cell count, early evaluation with PET and plasma TARC levels predict response in Hodgkin lymphoma. Cancer Med 5(3):398–406 170. Agostinelli C, Gallamini A, Stracqualursi L, Agati P, Tripodo C, Fuligni F et al (2016) The combined role of biomarkers and interim PET scan in prediction of treatment outcome in classical Hodgkin's lymphoma: a retrospective, European, Multicentre Cohort Study. Lancet Haematol 3(10):e467–e479 171. Lin C, Itti E, Haioun C, Petegnief Y, Luciani A, Dupuis J et al (2007) Early 18F-FDG PET for prediction of prognosis in patients with diffuse large B-cell lymphoma: SUV-based assessment versus visual analysis. J Nucl Med 48(10):1626–1632 172. Itti E, Lin C, Dupuis J, Paone G, Capacchione D, Rahmouni A et al (2009) Prognostic value of interim 18F-FDG PET in patients with diffuse large B-cell lymphoma: SUV-based assessment at 4 cycles of chemotherapy. J Nucl Med 50(4):527–533 7 Functional Imaging in Hodgkin Lymphoma 173. Biggi A, Bergesio F, Chauvie S, Bianchi A, Menga M, Fallanca F et al (2017) Concomitant semiquantitative and visual analysis improves the predictive value on treatment outcome of interim 18F-fluorodeoxyglucose/positron emission tomography in advanced Hodgkin lymphoma. Q J Nucl Med Mol Imaging. https://doi.org/10.23736/ S1824-4785 174. Cerci JJ, Trindade E, Pracchia LF, Pitella FA, Linardi CC, Soares J Jr et al (2010) Cost effectiveness of positron emission tomography in patients with Hodgkin’s lymphoma in unconfirmed complete remission or partial remission after first-line therapy. J Clin Oncol 28(8):1415–1421 175. Kobe C, Kuhnert G, Kahraman D, Haverkamp H, Eich HT, Franke M et al (2014) Assessment of tumor size reduction improves outcome prediction of positron emission tomography/computed tomography after chemotherapy in advanced-stage Hodgkin lymphoma. J Clin Oncol 32(17):1776–1781 176. Al-Nabhani KZ, Syed RF, Michopoulou S, Alkalbani J, Alkalbani JF, Afaq AF, Panagiotidis E, Meara C et al (2014) Qualitative and quantitative comparison of PET/CT and PET/MR imaging in clinical practice. J Nucl Med 55(1):88–94 177. Stecco AA, Buemi F, Iannessi AA, Carriero AA, Gallamini A (2018) Current concepts in tumor imaging with whole-body MRI with diffusion imaging (WB-MRI-DWI) in multiple myeloma and lymphoma. Leuk Lymphoma 59(11):2546–2556 178. Herrmann K, Queiroz M, Huellner MW, de Galiza BF, Buck A, Schaefer N et al (2015) Diagnostic performance of FDG-PET/MRI and WB-DW-MRI in the evaluation of lymphoma: a prospective comparison to standard FDG-PET/CT. BMC Cancer 15:1002 179. Martiat P, Ferrant A, Labar D, Cogneau M, Bol A, Michel C et al (1988) In vivo measurement of carbon-11 thymidine uptake in non-Hodgkin’s lymphoma using positron emission tomography. J Nucl Med 29(10):1633–1637 180. Shields AF, Mankoff DA, Link JM, Graham MM, Eary JF, Kozawa SM et al (1998) Carbon-11- thymidine and FDG to measure therapy response. J Nucl Med 39(10):1757–1762 181. Shields AF, Grierson JR, Dohmen BM, Machulla HJ, Stayanoff JC, Lawhorn-Crews JM et al (1998) Imaging proliferation in vivo with [F-18] FLT and positron emission tomography. Nat Med 4(11):1334–1336 182. Buchmann I, Neumaier B, Schreckenberger M, Reske S (2004) [18F]3′-deoxy-3′-fluorothymidine- PET in NHL patients: whole-body biodistribution and imaging of lymphoma manifestations—a pilot study. Cancer Biother Radiopharm 19(4):436–442 183. Buck AK, Bommer M, Stilgenbauer S, Juweid M, Glatting G, Schirrmeister H et al (2006) Molecular imaging of proliferation in malignant lymphoma. Cancer Res 66(22):11055–11061 184. Kasper B, Egerer G, Gronkowski M, Haufe S, Lehnert T, Eisenhut M et al (2007) Functional 143 185. 186. 187. 188. 189. 190. 191. 192. 193. 194. 195. diagnosis of residual lymphomas after radiochemotherapy with positron emission tomography comparing FDG- and FLT-PET. Leuk Lymphoma 48(4):746–753 Graf N, Herrmann K, den Hollander J, Fend F, Schuster T, Wester HJ et al (2008) Imaging proliferation to monitor early response of lymphoma to cytotoxic treatment. Mol Imaging Biol 10(6):349–355 Stern PH, Wallace CD, Hoffman RM (1984) Altered methionine metabolism occurs in all members of a set of diverse human tumor cell lines. J Cell Physiol 119(1):29–34 Nuutinen J, Leskinen S, Lindholm P, Soderstrom KO, Nagren K, Huhtala S et al (1998) Use of carbon-11 methionine positron emission tomography to assess malignancy grade and predict survival in patients with lymphomas. Eur J Nucl Med 25(7): 729–735 Kaste SC, Howard SC, McCarville EB, Krasin MJ, Kogos PG, Hudson MM (2005) 18F-FDG-avid sites mimicking active disease in pediatric Hodgkin’s. Pediatr Radiol 35(2):141–154 Kawase Y, Yamamoto Y, Kameyama R, Kawai N, Kudomi N, Nishiyama Y (2011) Comparison of 11C-methionine PET and 18F-FDG PET in patients with primary central nervous system lymphoma. Mol Imaging Biol 13(6):1284–1289 Rylova SN, Del PL, Klingeberg C, Tonnesmann R, Illert AL, Meyer PT et al (2016) Immuno- PET imaging of CD30-positive lymphoma using 89Zr-desferrioxamine-labeled CD30-specific AC-10 antibody. J Nucl Med 57(1):96–102 Rossi C, Kanoun S, Berriolo-Riedinger A, Dygai- Cochet I, Humbert O, Legouge C et al (2014) Interim 18F-FDG PET SUVmax reduction is superior to visual analysis in predicting outcome early in Hodgkin lymphoma patients. J Nucl Med 55(4):569–573 Specht L, Nordentoft AM, Cold S, Clausen NT, Nissen NI (1988) Tumor burden as the most important prognostic factor in early stage Hodgkin’s disease. Relations to other prognostic factors and implications for choice of treatment. Cancer 61(8):1719–1727 Song MK, Chung JS, Lee JJ, Jeong SY, Lee SM, Hong JS et al (2013) Metabolic tumor volume by positron emission tomography/computed tomography as a clinical parameter to determine therapeutic modality for early stage Hodgkin’s lymphoma. Cancer Sci 104(12):1656–1661 Kanoun S, Rossi C, Berriolo-Riedinger A, Dygai- Cochet I, Cochet A, Humbert O et al (2014) Baseline metabolic tumour volume is an independent prognostic factor in Hodgkin lymphoma. Eur J Nucl Med Mol Imaging 41(9):1735–1743 Mettler J, Muller H, Voltin CA, Baues C, Klaeser B, Moccia A et al (2018) Metabolic tumour volume for response prediction in advanced-stage Hodgkin lymphoma. J Nucl Med 2018:pii: jnumed.118.210047 8 Prognostic Factors Paul J. Bröckelmann and Lena Specht Contents 8.1 Historical Perspective 146 8.2 8.2.1 8.2.2 8.2.3 8.2.4 8.2.5 Prognostic Factors Definition and Use Types of Prognostic Factors Different End Points Types and Analyses of Prognostic Studies Predictive Factors 147 147 147 148 148 148 8.3 Prognostic Factors across Stages 149 8.4 Early-Stage Hodgkin Lymphoma 149 8.5 8.5.1 8.5.2 Advanced-Stage Hodgkin Lymphoma retreatment Prognostic Factors in Advanced-Stage Hodgkin Lymphoma P Interim PET as Prognostic Factor in Advanced-Stage Hodgkin Lymphoma Prognostic Indices in Advanced-Stage Hodgkin Lymphoma 150 152 8.5.3 8.6 8.6.1 8.6.2 8.6.3 rognostic Factors in Relapsed or Refractory P Hodgkin Lymphoma Patients Treated for r/r HL with Conventional Treatment Treatment with High-Dose Chemotherapy and Autologous Stem Cell Transplantation Patients’ Prognostic Indices or Scores in r/r HL Treated with Novel Agents 153 153 155 155 157 158 P. J. Bröckelmann (*) Department I of Internal Medicine and German Hodgkin Study Group (GHSG), University Hospital of Cologne, Köln, Germany e-mail: paul.broeckelmann@uk-koeln.de L. Specht Department of Oncology, Section 3994, The Finsen Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark e-mail: lena.specht@regionh.dk © Springer Nature Switzerland AG 2020 A. Engert, A. Younes (eds.), Hodgkin Lymphoma, Hematologic Malignancies, https://doi.org/10.1007/978-3-030-32482-7_8 145 P. J. Bröckelmann and L. Specht 146 8.6.4 Prognostic Factors for Treatment with Novel Agents in r/r HL 158 8.7 Conclusion and Future Aspects 159 References Abbreviations ABVD Adriamycin, bleomycin, vinblastine, dacarbazine ASCT Autologous stem cell transplant BEACOPPescBleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisolone, escalated BNLI British National Lymphoma Investigation BV Brentuximab vedotin CALGB Cancer and Leukemia Group B cfDNA Cell-free DNA CRP C-reactive protein CS Clinical stage EBMTEuropean Society for Blood and Marrow Transplantation ECOGEastern Cooperative Oncology Group EFS Event-free survival EN Extranodal EORTC European Organization for Research and Treatment of Cancer ESR Erythrocyte sedimentation rate FDG2-[18F]fluoro-2-deoxy-d-glucose FF2F Freedom from second failure FFP Freedom from progression GELA Groupe d’Etudes des Lymphomes de l’Adulte GHSG German Hodgkin Lymphoma Study Group HDCT High-dose chemotherapy HL Hodgkin lymphoma HRS Hodgkin-Reed-Sternberg IPS International Prognostic Score LDH Lactate dehydrogenase LMM Large mediastinal mass LP Lymphocyte predominant 160 MHCMajor histocompatibility complex MOPPMechlorethamine, vincristine, procarbazine, prednisolone MTV Metabolic tumour volume NCI-C National Cancer Institute of Canada NCI-USNational Cancer Institute of the United States NS Nodular sclerosis OS Overall survival PD-1 Programmed cell death protein 1 PD-L1 Programmed death ligand 1 PET Positron emission tomography PFS Progression-free survival PR Partial remission r/r Relapsed or refractory RT Radiation therapy SWOG Southwest Oncology Group TAM Tumour-associated macrophages TARCThymus and activation regulated chemokine TNF Tumour necrosis factor TTR Time to relapse 8.1 Historical Perspective The concept that Hodgkin lymphoma (HL, then called Hodgkin’s disease) passes through successive clinical stages with increasing spread of the disease and progressive worsening of prognosis was developed early on [1]. Different staging classifications were proposed based on the anatomic extent of disease [2–8]. A consensus was reached at the Workshop on the Staging of Hodgkin’s Disease at Ann Arbor in 1971 [9], and the Ann Arbor staging classification was universally adopted. It still remains the basis for the Prognostic Factors Fig. 8.1 Five-year relative survival according to Ann Arbor stage for patients in the US National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program treated in the period 1975–2015 (Reprinted with permission from Noone et al. [18]) 147 5-Year Relative Survival 100 92.3% 93.4% 90 83.0% 80 Percent Surviving 8 82.7% 72.9% 70 60 50 40 30 20 10 0 Stage I Stage II Stage III Stage IV Unknown Stage evaluation of patients with HL, and its prognostic significance has been documented in numerous studies of patients treated with different treatment modalities [10–17]. Five-year relative survival according to Ann Arbor stage for patients treated between 1975 and 2015 from the US National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program is shown in Fig. 8.1 [18]. However, the extent of disease varies within the Ann Arbor stages leading to variations in prognosis. A modification of the Ann Arbor classification was proposed at the Cotswold meeting, incorporating a designation for number of sites and bulk [19]. This modification has not been universally adopted. An update of the staging system was introduced in 2014 with the Lugano classification [20]. Therein a single nodal mass of 10 cm or greater than a third of the transthoracic diameter at any level of thoracic vertebrae as determined by CT was retained as the definition of bulky disease. PET/CT was designated as the preferred method of staging, obviating the need for bone marrow biopsies. Numerous other prognostic factors for different Ann Arbor stages, disease presentations, treatment approaches, and outcomes have been introduced, and varying combinations of these factors are currently being used by different centres and study groups. 8.2 Prognostic Factors 8.2.1 Definition and Use Prognostic factors are variables measured in individual patients that offer a partial explanation of the outcome heterogeneity of a given disease [21]. They are important in clinical practice for allocating patients into different risk groups, for selection of treatment strategy, and as an aid in patient counselling [22]. However, it is important to realise that prediction is very uncertain for the individual patient. Statements of probability can be made, but even these will be more accurate for groups of patients than for individuals [23]. Prognostic factors can also be used in the design of clinical trials to define eligibility criteria and strata to ensure comparability of treatment groups [21–24]. However, prognostic factors are rarely sufficiently explanatory to justify the comparison of treatments by use of nonrandomised data [25, 26]. 8.2.2 Types of Prognostic Factors Prognostic factors are divided into tumour-related factors, host-related factors, and environment- related factors [22]. Tumour-related factors P. J. Bröckelmann and L. Specht 148 include those directly related to the presence of the tumour or its effect on the host, reflecting tumour pathology, anatomic extent, or tumour biology. Host-related factors include factors that are not directly related to the tumour but which may significantly influence outcome, such as demographic characteristics and co-morbidity. Environment-related factors include factors outside the patient, such as socio-economic status and access to and quality of health care. The values of prognostic factors are generally assumed to be known from the outset, before start of treatment, so-called fixed covariates. However, other important prognostic variables may only be known later, such as time to response, toxicity of treatment, and the value of presumed markers. These are time-dependent covariates. They may be important for answering biological questions, but they should not be applied for adjustment for treatment comparison, as they are themselves affected by treatment [21–23]. 8.2.3 Different End Points Different outcomes may be of interest in analyses of prognostic factors. Overall survival and progression-free survival are usually analysed, but others may be relevant, e.g. disease-free survival for early-stage patients as nearly all patients achieve remission. For each end point, there must be clear information on the point in time from which it is measured and the clinical characteristics of events and censoring. International guidelines have been published [27]. 8.2.4 Types and Analyses of Prognostic Studies Three different study phases of prognostic factors have been proposed, beginning with phase I early exploratory analyses to identify potential markers and generate hypotheses for further investigation. Phase II studies are exploratory studies attempting to use values of a proposed prognostic factor to discriminate between high- and low-risk patients. Phase III studies are large, confirmatory studies based on prespecified hypotheses involving one or a few new factors, and the purpose of these studies is to determine how much the new factor adds to the predictive power of already accepted factors [24, 28]. A useful prognostic factor must be significant, independent, and clinically important [29]. Many variables may be prognostic in univariate analysis. However, different variables are likely to be interrelated. The important question is whether a particular variable adds useful information to what is already known. Multiple regression analysis is commonly employed to determine whether a variable has independent significance when other known variables are taken into account. This kind of analysis may form the basis for the development of a prognostic model and a risk score or risk groups [28]. The Cox proportional hazards regression model is most commonly used when time-toevent outcomes are of interest [30]. The selection of variables for the final model is usually done by stepwise selection. By play of chance, different factors may be selected in different studies. An important additional analysis for a new marker is therefore to determine its prognostic ability in a model including all previously defined prognostic factors [28, 31]. Differences may also be due to small sample size, different assay techniques, different cut points for variables, inclusion of different subsets of patients, and different study end points. 8.2.5 Predictive Factors Predictive factors are patient characteristics that identify subgroups of patients with different outcomes as a consequence of a given treatment. Hence a predictive factor identifies subgroups of treated patients having different outcomes, whereas a prognostic factor identifies subgroups of untreated patients having different outcomes. A factor that is predictive of outcome after one particular treatment may not be predictive for another treatment. 8 Prognostic Factors 8.3 149 rognostic Factors across P Stages [52–55]. Hopefully this problem will be solved soon, resulting in a simple method that will allow measuring the total metabolic tumour volume. This should be closely related to the total tumour burden and become a practical and clinically useful method for dividing patients with HL into prognostic subgroups (Fig. 8.2). Most important prognostic factors in HL, irrespective of stage, are correlated with and provide indirect measures of the patient’s total tumour burden. The total tumour burden is the most important prognostic factor, rendering most other prognostic factors insignificant in multivariate analysis. This was demonstrated by semi- 8.4 Early-Stage Hodgkin quantitative methods, based on a combination of Lymphoma the number of involved lymph node regions and the volume of disease in individual regions, in From early studies in Hodgkin lymphoma, it was patient materials treated even before staging with evident that the number of involved regions and CT scans was introduced [32–39]. When patient size of mediastinal disease, B symptoms, histomaterials staged with CT scans became available, logical subtype, age, gender, ESR, haemoglobin, it became possible to directly contour and quanti- and serum albumin were prognostically signifitate the total tumour volume in each individual cant [14, 56–65]. Table 8.1 lists the established patient, and the pivotal prognostic role of the total tumour burden was confirmed [40–46]. However, these methods for estimating the total Table 8.1 Prognostic factors in early-stage HL tumour burden were too laborious to be imple- Tumour burden Number of involved lymph node regions mented into clinical practice. HL is a highly FDG-avid tumour, and the total Large tumour mass, particularly mediastinal B symptoms volume of the PET-positive lymphoma tissue (the Histological subtype metabolic tumour volume) is highly correlated Age with the total tumour burden. Hence, studies are Gender now demonstrating the prognostic relevance of Erythrocyte sedimentation rate (ESR) the metabolic tumour volume [47–51]. The pre- Haemoglobin ferred method for measuring the baseline meta- Serum albumin bolic tumour volume has not yet been agreed (early interim FDG-PET scan) 100 TMTV0 ≤225ml 80 DSS probability (%) PFS probability (%) 100 60 40 TMTV0 >225ml 20 TMTV0 ≤225ml 80 60 40 TMTV0 >225ml 20 P= 0.001 P= 0.0015 0 0 0 10 20 30 40 50 Time (months) 60 70 Fig. 8.2 Progression-free (PFS) and disease-specific survival (DSS) for 59 patients with all stages of HL divided into low and high total metabolic tumour volume, i.e. < or 0 10 20 30 40 50 Time (months) 60 70 >225 ml (Reprinted with permission from Kanoun et al. 2014 [49]) P. J. Bröckelmann and L. Specht 150 prognostic factors in early-stage HL. Based on the most important factors, different centres and groups divided early-stage patients into favourable and unfavourable. Table 8.2 shows the factors and risk groups defined by some of the major groups. Although the factors included in these risk group definitions are fairly similar, the risk group definitions vary making comparisons between patient materials difficult. Treatment of early-stage patients is tailored according to prognostic subgroups. Thus, in many studies patients are selected, making the detection of prognostic factors difficult. Most of the important prognostic factors are correlated providing indirect measures of the patient’s total tumour burden [36, 39, 62]. Functional imaging with FDG-PET has become an important part of staging and treatment evaluation of lymphomas. An early interim FDG-PET scan after one or two cycles of chemotherapy has been shown to be highly predictive of outcome after combined modality treatment [66–71]. However, in early-stage disease, there are many false-positive results, the predictive value depends on the chemotherapy regimen used, and the majority of the patients with interim PET positivity were cured with combined modality therapy, yielding a positive predictive value of only 15% [72]. The negative predictive value is very high in earlystage disease, which would be expected in a disease with a very good prognosis. In fact, because over 90% of patients with early-stage disease are cured with standard treatment, the added information from a negative interim PET scan is actually very limited [73, 74]. The early interim FDG-PET scan may be regarded as an in vivo test of the chemosensitivity of disease. As the result of the scan is not known at the outset, there is a methodological problem with this test. Strictly speaking, outcome according to the result of an early interim FDG-PET scan should only be measured from the time when it is available, and it should be regarded more as a predictive factor indicating the sensitivity to a particular treatment rather than as a usual prognostic factor. From a clinical point of view, it would be better to predict the outcome with a given regimen up front rather than having to initially administer possibly ineffective or too intensive treatment. The total metabolic tumour volume (MTV) as a surrogate for the total tumour burden seems promising in this respect. Furthermore, recent research into molecular abnormalities in either tumour cells or non-malignant background cells has demonstrated numerous biomarkers, some of which will hopefully allow individualization of treatment up front [75–91]. However, for a new prognostic factor to be proven useful, it needs to be demonstrated to show independent significance when the already known factors, in particular the total tumour burden, are taken into account. The standard treatment for early-stage disease is combined modality treatment. Recently, chemotherapy alone has been used, resulting in a moderate increase in the risk of relapse. Prognostic factors in this group of patients have not been analysed in detail as large cohorts of patients with reasonable follow-up are not yet available. 8.5 Advanced-Stage Hodgkin Lymphoma Patients presenting in stage III/IV are universally considered as advanced-stage requiring systemic treatment, eventually followed by consolidative RT in selected cases. Patients with stage IIB and additional risk factors such as extranodal disease (EN) or a large mediastinal mass (LMM) are additionally regarded advanced-stage by some study groups or centres for the purpose of first- line therapy. Large data sets are important to reliably assess the independent contributions of single routinely documented clinical prognostic factors and two very large data sets resulted from international cooperation: The International Database on Hodgkin’s Disease set up in 1989 combined >14,000 individual patient data across all stages from 20 study groups in the MOPP era [14]. In 1995, the International Prognostic Factors Project on advanced Hodgkin lymphoma combined data of 5141 advanced-stage patients mainly treated with doxorubicin-containing regimen [92]. More CS I or CS IIA with ≥1 risk factors CS IIB with (c) or (d) but without (a) and (b) GHSG (a) Large mediastinal mass (b) Extranodal disease (c) ESR ≥ 50 without B symptoms or ≥30 with B symptoms (d) ≥3 nodal areas CS I–II without risk factors EORTC (a) Large mediastinal mass (b) Age ≥ 50 years (c) ESR ≥ 50 without B symptoms or ≥with B symptoms (d) ≥4 nodal areas CS I–II (supradiaphragmatic) without risk factors CS I–II (supradiaphragmatic) with ≥1 risk factors NCI-C and ECOG (a) Histology other than LP/NS (b) Age ≥ 40 years (c) ESR ≥ 50 (d) ≥4 nodal areas CS I–II without risk factors CS I–II with ≥1 risk factors CS I–II without risk factors CS I–II with ≥1 risk factors Stanford (a) B symptoms (b) L arge mediastinal mass GHSG German Hodgkin Study Group, EORTC European Organization for Research and Treatment of Cancer, NCI-C National Cancer Institute of Canada, ECOG Eastern Cooperative Oncology Group Unfavourable Favourable Risk factors Table 8.2 Criteria for favourable vs. unfavourable early-stage HL as defined by different centres and cooperative study groups 8 Prognostic Factors 151 P. J. Bröckelmann and L. Specht 152 recent studies focussed on disease activity measured by interim and/or end-of-treatment PET to further individualize treatment. 8.5.1 Pretreatment Prognostic Factors in Advanced-Stage Hodgkin Lymphoma The most important patient-related prognostic factor for overall survival (OS) in advanced-stage HL is age [93–97]. Elderly patients (>60 years) are often excluded from clinical trials [98]. Prevalence of co-morbidity is associated with age and treatment-related mortality is increased [99]. In patients up to 65 years, age >45 years is an independent prognostic factor for freedom from progression. The impact of age is amplified in overall survival as compared to progression-free survival due to compromised results of salvage treatment in elderly relapsed patients [100]. Male gender is another independent, although quantitatively moderate, adverse patient-related prognostic factor within advanced stages [14, 92, 101, 102]. In terms of disease-related factors, tumour burden either quantified from conventional or PET imaging is a main determinant of prognosis [39–41, 62, 103]. As previously outlined, MTV is increasingly being recognised as pre-therapeutic prognostic factor but still rarely measured routinely. Stage IV marks dissemination of the disease to extranodal sites and is independently prognostic within advanced-stage disease [14, 92]. A particularly bad prognosis for bone marrow, lung, or liver involvement could not be confirmed. It thus remains controversial whether certain disease locations or the number of involved extranodal sites carries independent prognostic value within stage IV disease. Several haematological and biochemical laboratory parameters form a cluster of interrelated prognostic indicators that mirror both tumour burden and inflammatory processes [75]. These factors include decreased serum albumin and haemoglobin levels as well as an elevated ESR, LDH, C-reactive protein (CRP), and alkaline phosphatase, which are correlated with one other as well as with the presence of B symptoms and tumour burden. Leukocyte and lymphocyte counts form a second correlation cluster of laboratory parameters; in addition, leucocytosis and lymphocytopenia have an independent prognostic impact [92]. A plethora of biological parameters such as levels of cytokines released by HRS cells, soluble forms of membrane-derived antigens, and cell- free tumour DNA have been investigated for prognostic value not confined to advanced-stage disease. Many of these studies were done in rather small data sets, and findings are often not yet integrated with other clinical or imaging factors in multivariate analysis. The soluble form of the CD30 molecule (sCD30) is released by HRS cells and is detectable in the serum of virtually all untreated patients. It maintains independent prognostic significance in multivariate analysis in moderately sized data sets [78, 104–106]. The thymus and activation-regulated chemokine (TARC or CCL117) plays a role in the pathogenesis of HL and correlates with disease burden and outcome [107]. A correlative analysis of the recent randomized phase III ECHELON-1 trial comparing ABVD and BV-AVD could not confirm a prognostic role for sCD30 or TARC since neither of the two parameters correlated with early or end-of-treatment response nor PFS [108]. The relevance of cytokine levels such as IL-1RA, IL-2R, IL-6, IL-10, or tumour necrosis factor (TNF) requires further investigation [78, 109, 110] as does the role of elevated β2- microglobulin [111]. Circulating cell-free tumour DNA (cfDNA) recently gained attention across various tumour types since it potentially allows minimally invasive monitoring of disease activity over the course of treatment as well as genetic assessment of the malignancy [112]. After a proof-of-concept study for HL was published [113], very recent studies highlight the prognostic potential of cfDNA, especially in correlation with disease status by PET [114, 115]. Focussing on tumour architecture and composition, several histopathological markers in tumour tissue either expressed by HRS or reactive bystander cells were identified. High density of CD68+ macrophages has been shown to be adversely prognostic with ABVD treatment [89, 8 Prognostic Factors 153 116]. Tumour-associated macrophages (TAM) together with cells involved in a TH1 immune response possibly create an inflammatory environment favouring rapid lymphoma proliferation. A recent analysis revealed frequent 9p24.1 amplifications in advanced-stage cHL which were associated with poorer PFS in ABVD- treated patients [117]. In order to obtain a method usable in clinical practice, a 23-gene expression signature was shown to be predictive in advanced- stage ABVD-treated patients [88]. However, further validation in clinical trials including PET-adapted or BEACOPP-based therapy is required. 8.5.2 I nterim PET as Prognostic Factor in Advanced-Stage Hodgkin Lymphoma An early interim FDG-PET scan after two cycles of chemotherapy (PET-2) has been shown to be highly predictive of outcome in advanced-stage HL a decade ago [68, 118–120]. In a large study of advanced-stage patients treated with ABVD, the prognostic value of PET-2 completely overshadowed the role of the International Prognostic Score (IPS) [121]. Figure 8.3 shows PFS according to the IPS and the PET-2 result. Within the last years, individualized treatment guided by PET-2 was investigated in several phase III trials. Within the UK-led RATHL trial, 8.5.3 Progression-Free Survival 1.0 0.8 0.6 IPS 0-2, PET2 negative IPS 0-2, PET2 positive IPS 3-7, PET2 negative IPS 3-7, PET2 positive 0.4 0.2 Log-rank P = ≈ 0 0 PFS and OS were superior in PET-2-negative patients as compared to PET-2-positive patients, despite de-escalation from ABVD to AVD or escalation from ABVD to BEACOPPescalated, respectively [122]. In PET-2-negative patients, only stage IV disease and the IPS but no other factors such as bulky disease, PET score by Deauville, or B symptoms retained prognostic significance for PFS. In contrast, PET-2 status was not prognostic for PFS in the GHSG HD18 trial [123] as shown in Fig. 8.4. Neither addition of rituximab to BEACOPPescalated in the PET-2-positive patient nor reduction from 6–8×BEACOPPescalated to 4×BEACOPPescalated did relevantly change PFS or OS for these different treatment arms (Fig. 8.5) [123]. Similar observations were made in the French AHL2011 trial, which investigated de- escalation to 4xABVD in PET-2-negative patients after 2×BEACOPPescalated [124]. These findings underline the poor positive predictive value of a positive PET-2 in patients initially treated with BEACOPPescalated. On the other hand, the improved negative predictive value of a negative PET-2 in this group of patients has to be compared to those initially treated with ABVD. Of note, post-hoc analyses of the UK RATHL trial showed very good inter-observer comparability, highlighting the feasibility of utilizing PET-2-guided therapy in routine clinical care [125] . 1 2 3 4 5 Time (years) Fig. 8.3 PFS in 260 patients with advanced-stage disease according to the IPS and PET-2 status after 2×ABVD (Reprinted with permission from Gallamini et al. [121]) Prognostic Indices in Advanced-Stage Hodgkin Lymphoma Prognostic indices for advanced HL are clinically important to select patients prior to initiation of first-line treatment who may be over- or undertreated by standard therapeutic approaches. Over the last decades, several groups developed prognostic indices or scores based on a few hundred cases trying to define high-risk groups. Most scores combined age, disease extent, and laboratory markers, but only a prognostic model for OS developed by Gobbi et al. based on the following seven factors received P. J. Bröckelmann and L. Specht 154 PET-2 negative PET-2 positive Non-randomised 100 Progression-free surival (%) 90 80 70 60 3-year estimate (95% CI) 50 PET-2 negative 40 5-year estimate (95% CI) 93·5% (91·9–95·1) 91·4% (89·5–93·4) 92·5% (90·7–94·3) 88·3% (85·8–90·8) 30 Non-randomised 77·6% (68·6–86·6) 77·6% (68·6–86·6) 20 Overall 92·3% (91·1-93·5) 89·4% (87·9-91·0) 10 Median observation time 52 months (IQR 32–67) PET-2 positive 0 0 Number at risk (number censored) PET-2 negative 1010 (0) PET-2 positive 948 (0) Non-randomised 115 (0) 12 24 36 48 60 921 (63) 854 (62) 72 (31) 845 (118) 766 (131) 61 (37) 685 (265) 600 (284) 47 (49) 548 (396) 476 (398) 35 (61) 385 (553) 276 (588) 24 (72) Fig. 8.4 PFS according to PET-2 status after 2×BEACOPPescalated in 2073 patients with advanced-stage treated within the HD18 trial (Reprinted with permission from Borchmann et al. [123]) 8×eBEACOPP or 6xeBEACOPP 4×eBEACOPP 100 Progression-free surival (%) 90 80 70 60 3-year estimate (95% CI) 50 40 30 8×eBEACOPP or 6×eBEACOPP 91·7% (89·0 to 94·4) 90·8% (87·9 to 93·7) 4×eBEACOPP 95·3% (93·3 to 97·3) 92·2% (89·4 to 95·0) 3·6% (−0·2 to 6·9) −1·4% (−2·7 to 5·4) Difference 20 Hazard ratio (95% CI) 10 5-year estimate (95% CI) 0·79% (0·50 to 1·24) Median observation time 55 months (IQR 36–70) 0 0 12 24 36 48 60 411 (21) 444 (22) 378 (45) 412 (43) 310 (102) 334 (119) 247 (164) 269 (180) 164 (246) 198 (246) Number at risk (number censored) 8×eBEACOPP or 6×eBEACOPP 446 (0) 4×eBEACOPP 474 (0) Fig. 8.5 PFS in 920 PET-2-negative patients treated with a total of 6–8× vs. 4×BEACOPPescalated in the HD18 trial (Reprinted with permission from Borchmann et al. [123]) 8 Prognostic Factors general acceptance: stage, age, histology, B symptoms, serum albumin, sex, and involved area distribution (infradiaphragmatic disease or >3 supradiaphragmatic areas) [101]. Some years later, the International Prognostic Factors Project on advanced-stage HL focussed on FFP [92]. Individual patient data were collected from 23 centres and study groups including 5141 advanced-stage HL patients who were treated mainly with doxorubicin-containing chemotherapy with and without radiotherapy. A prognostic score was developed from this data set in patients up to 65 years of age. The score is a simple count of seven binary adverse prognostic factors (Table 8.3): This prognostic model, termed the “International Prognostic Score” (IPS), predicts 5-year tumour control rates in the range of 45–80%. Each additional factor reduces the prognosis by about 8%. Figure 8.6 shows the FFP according to the number of adverse prognostic factors. Since its publication, the IPS has performed reasonably well in independent data sets [126– 131], including patients treated with intensified BEACOPP chemotherapy, where outcome uniformly improved in all IPS groups with persisting but quantitatively reduced differences [126, 130]. Comparison of several prognostic models [94, 128] revealed that none of the models including the IPS are able to select either a very low-risk group (e.g. <10% failure rate) or a substantial very high-risk group (>50%). The prognostic models thus discriminate only between low-risk and high-risk patients (e.g. IPS ≤2 vs. IPS >2). A more recent analysis verified the prognostic value Table 8.3 Adverse prognostic factors incorporated in the International Prognostic Factors Project score for FFP in advanced-stage HL Age ≥ 45 years Male sex Stage IV disease Haemoglobin <10.5 g/dl Serum albumin <4.0 g/dl Leucocytosis ≥15 × 109/l Lymphocytopenia <0.6 × 109/l or <8% of white blood cell count 155 of the original IPS-7 in patients treated with either ABVD or Stanford V within the multicentre US E2496 trial, though with narrowed prognostic range. Based on the three prognostic factors age, stage, and haemoglobin identified by multivariable analysis, a simple IPS-3 with better discrimination for freedom from progression and overall survival (OS) was developed (Fig. 8.7) [132]. Several authors tried to extend the IPS beyond advanced stages. The IPS works nicely to predict outcome after autologous haematopoietic stem cell transplantation [133]. It appears to be moderately predictive in early and intermediate stages, extending the factor stage IV to include any extranodal disease [57, 134]. 8.6 Prognostic Factors in Relapsed or Refractory Hodgkin Lymphoma 8.6.1 atients Treated for r/r HL P with Conventional Treatment Patients relapsing after initial treatment with chemotherapy only or combined modality therapy, whether for limited or advanced disease, historically had a poor prognosis with conventional chemotherapy, obtaining durable remissions in only 10–30% of cases [135–140]. In this setting, the extent and duration of an initial remission (i.e. time-to-relapse, TTR) is the most important prognostic factor for outcome after relapse. Patients who never achieve a remission (i.e. refractory or primary progressive disease) have an extremely poor prognosis, while patients who relapse within or after 12 months of completion of therapy have an intermediate or relatively good prognosis, respectively [135–138, 140, 141]. But even for the latter, long-term outlook is poor with historic conventional chemotherapy and dismal in patients with second or higher relapse [142–144]. Figure 8.8 shows survival curves for patients relapsing after initial chemotherapy divided into these three prognostic groups [145]. In addition to TTR, the extent of disease at relapse is also independently significant for P. J. Bröckelmann and L. Specht 156 1.0 # of factors .9 % freedom from progression Fig. 8.6 Freedom from progression according to the number of adverse prognostic factors (see Table 8.3) for 1618 patients with advanced- stage HL in the International Prognostic Factors Project (Reprinted with permission from Hasenclever and Diehl [81]) .8 0 : N=115 (7%) 1 : N=360 (22%) .7 2 : N=464 (29%) .6 3 : N=378 (23%) .5 4 : N=190 (12%) 5+: N=111 (7%) .4 .3 .2 .1 0.0 0 1 2 3 4 5 6 7 years OS by PS-3 0.6 0.6 0.8 0.8 1.0 1.0 FFP by PS-3 OS Log rank test P < 0.0001 0.4 0.4 FFP Log rank test P = 0.0001 N 83 ± 2 74 ± 3 68 ± 5 63 ± 10 PS-3 = 0 PS-3 = 1 PS-3 = 2 PS-3 = 3 5-year OS (%) 474 275 82 23 95 ± 1 85 ± 2 75 ± 5 52 ± 10 0.0 0.0 0.2 5-year FFP (%) 474 275 82 23 0.2 N PS-3 = 0 PS-3 = 1 PS-3 = 2 PS-3 = 3 0 2 4 6 8 10 12 Years 0 2 4 6 8 10 12 Years Fig. 8.7 FFP and OS according to IPS-3 among 854 patients with advanced-stage HL in the E2496 trial (Reprinted with permission from Diefenbach et al. [132]) prognosis. Advanced stage, extranodal disease, and more than three involved sites at relapse are adverse prognostic factors [100, 135, 136, 140, 146]. Age, performance status, histology other than nodular sclerosis, B symptoms at relapse, and a low haemoglobin have also been shown to be significant [100, 135, 137, 138, 140, 141, 146]. Prognostic factors which have been shown to be independently significant for outcome after HL relapse treated with conventional chemotherapy are summarised in Table 8.4. A subgroup of patients with relapsed or refractory HL (r/r HL) have anatomically limited disease. For selected patients in this subgroup, RT with or without additional chemotherapy offers some chance of durable remission [138, 147–150]. Prognostic factor analyses indicate that patients suitable for this kind of relapse treatment are those relapsing exclusively in supradiaphragmatic nodal sites, with no B symptoms at relapse, and after a disease-free interval of >12 months [147, 148, 151]. In patients with 8 Prognostic Factors 157 1.0 Probability 0.8 0.6 late relapse 52/169 early relapse 64/138 0.4 primary progressive 129/206 0.2 p < 0,0001 0.0 0 12 24 36 48 60 Months 72 84 96 108 120 Fig. 8.8 OS of patients with primary progressive, early relapse, or late relapse of HL, treated in GHSG trials from 1988 to 1999 primarily with conventional salvage (Reprinted with permission from Josting and Schmitz [145]) Table 8.4 Independent prognostic factors for outcome in r/r HL treated with conventional chemotherapy Extent and durability of first remission (TTR) Extent of disease at relapse (relapse stage, extranodal relapse, ≥3 sites of relapse) B symptoms at relapse Haemoglobin at relapse Histology Age Performance status these favourable characteristics, durable remission with RT may be achieved in up to 50% of cases. 8.6.2 Treatment with High-Dose Chemotherapy and Autologous Stem Cell Transplantation High-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) is superior to conventional chemotherapy in r/r HL [152, 153]. Hence, it is the preferred treatment in relapsed eligible patients and current standard of care. Similar to treatment with conventional chemotherapy, a number of prognostic factors were identified decades ago and are still independently significant for outcome. The chemosensitivity of the disease is extremely important. Thus, the response to initial or salvage therapy, the duration of initial remission, and the number of prior failed regimens have been shown to be associated with outcome [154–161]. Evaluation of response to salvage treatment before HDCT by PET further refines prognostication [162–167]. The disease burden before transplantation is another important prognostic factor, and measures reflecting tumour burden such as stage of disease and bulky or extranodal disease at salvage have been shown to be independently significant [145, 154, 161, 168]. B symptoms, low haemoglobin, and elevated serum LDH at relapse are also significant [154, 157, 162, 169, 170]. A poor performance status is an important adverse prognostic feature [155, 159, 171], whereas age has not been significant in most series, probably due to the fact that most patients are relatively young as required by the intensive HDCT + ASCT approach [161, 172–176]. Of note, paediatric patients have the same outcome as adults [177]. P. J. Bröckelmann and L. Specht 158 Table 8.5 Independent prognostic factors for outcome after HDCT + ASCT in r/r HL Chemosensitivity of HL Response to initial or salvage therapy Duration of initial remission (TTR) Number of failed prior regimens FDG-PET after salvage and before HCT + ASCT Disease burden before salvage Stage of disease in r/r HL Bulky disease in r/r HL Extranodal r/r HL B symptoms at r/r HL Haemoglobin at r/r HL Serum lactate dehydrogenase (LDH) at r/r HL The seven factors included in the IPS for advanced-stage HL have also been examined in r/r HL and are at least partially applicable [133, 178]. The prognostic factors known to be independently significant for outcome after high-dose chemotherapy and stem cell transplantation are shown in Table 8.5. For patients with disease recurrence after ASCT, prognosis was poor historically. Refractory disease at second-line treatment and short disease-free interval after ASCT are very poor prognostic factors [179–182]. 8.6.3 atients’ Prognostic Indices or P Scores in r/r HL Treated with Novel Agents Over the last years, several studies aimed at combining individual risk factors in prognostic scores developed by multivariable analyses to improve clinical applicability. An early prognostic score based on the equally weighted three clinical risk factors haemoglobin <10.5 g/dl and <12.0 g/dl in female and male patients, respectively, clinical stage III/IV, and TTR <12 months was established by an analysis of 422 patients relapsing after treatment in GHSG trials between 1988 and 1999. Four-year FF2F was estimated at 65%, 35%, and 25% for low-, intermediate-, and high-risk patients, respectively [183]. In a more recent analysis of the European HDR2 trial, only stage IV disease but not stage III or III/IV at relapse retained prognostic significance; 3-year PFS was estimated at 81% and 14% for the most favourable and unfavourable risk groups with zero or all three risk factors, respectively [184]. Based on EBMT registry data and the four factors Karnofsky performance score < 90%, chemotherapy resistance prior to ASCT, ≥3 chemotherapies pre-ASCT, and extranodal disease, a different risk score was proposed and externally validated. Four-year PFS for the low-, intermediate-, and high-risk group were 71%, 60%, and 42%, respectively [185]. In a very recent international effort, a simple externally validated prognostic score in contemporarily treated patients within or outside clinical trials was developed [171]. Equal weighting of the five factors stage IV disease, TTR ≤ 3 months, ECOG performance status ≥ 1, bulk ≥ 5 cm, and inadequate response to salvage chemotherapy (i.e. <PR or PET positivity) thereby resulted in optimal prognostication of both PFS and OS after ASCT (Fig. 8.9). 8.6.4 Prognostic Factors for Treatment with Novel Agents in r/r HL The anti-CD30 antibody-drug conjugate brentuximab vedotin (BV) was one of the first drugs in decades approved for the treatment of r/r HL based on acceptable toxicity and high response rates in the pivotal phase II trial [186]. Subgroup analyses according to potential risk factors did not reveal any unfavourable risk groups in terms of response rates or PFS. A recent trial investigating BV as salvage therapy prior to ASCT identified MTV in addition to refractory disease as relevant prognostic factors for event-free survival (EFS) in multivariable analysis [50]. When administering BV as consolidative therapy after ASCT, a sustained 5-year PFS benefit compared to placebo was seen across risk groups with a pronounced difference in patients with any ≥2 risk factors from a variety of potential single risk factors [187]. 8 Prognostic Factors 159 1.0 0.9 0.8 PFS rate 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0.0 0 12 1 36 24 2 3-5 48 60 72 84 Time [months] 1.0 Overall survival [months] rate 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0.0 0 12 24 1 36 2 3-5 48 60 72 84 Time [months] Fig. 8.9 PFS and OS after ASCT for r/r HL according to the number of risk factors present (Adapted with permission from Bröckelmann et al. 2017 [171]) More recently, the anti-PD1 antibodies nivolumab and pembrolizumab were approved for r/r cHL due to high response rates and exceptional tolerability in the pivotal phase II trials [188, 189]. Across both trials, also heavily pretreated patients with unfavourable disease characteristics responded to therapy and achieved relatively long PFS. Exploratory analyses in r/r cHL patients treated with nivolumab revealed 9p24.1 alterations in virtually all patients and a correlation of PFS with the 9p24.1 genetic categories (e.g. amplification or copy gain) as well as PD-L1 expression by the HRS cells. In addition, sustained MHC class II expression on HRS cells was associated with superior response rates and PFS in patients treated >12 months after ASCT. As expected, patients achieving a PR or CR had superior PFS to non-responders [190]. 8.7 Conclusion and Future Aspects As demonstrated above, a large number of variables have been shown to possess prognostic significance in HL, both at initial presentation and at relapse or progression. Most of these variables are correlated with the total tumour burden, P. J. Bröckelmann and L. Specht 160 which has hitherto been too cumbersome to measure for use in clinical practice. However, the metabolic tumour volume, measured by FDG- PET, is highly correlated with the total tumour burden and may become an important and clinically useful prognostic tool in the future. Today, treatment is tailored to risk groups defined by prognostic factors, with less intensive therapies for patients with favourable disease in order to reduce toxicity and increasing treatment intensity for patients with unfavourable characteristics with the aim of increasing cure rates. Different centres and groups use slightly differing criteria for initial treatment selection, which makes direct comparisons challenging and some form of international harmonisation desirable. Early interim functional imaging by FDG-PET as a marker for treatment sensitivity allows individualized treatment in routine clinical care of advanced-stage HL. In early-stage disease, its role is less clear. Molecular abnormalities in either tumour cells or their microenvironment as well as circulating cell-free DNA may potentially prove to be powerful prognostic markers. Integration of these biomarkers will hopefully enable refined therapeutic approaches better tailored to individual disease activity and risk of treatment failure. With the advent of novel agents, drug-specific prognostic or predictive factors are of increasing interest to stratify treatments and minimize potentially harmful and expensive exposure. 7. 8. 9. 10. 11. 12. 13. 14. 15. References 1. Reed DM (1902) On the pathological changes in Hodgkin's disease, with especial reference to its relation to tuberculosis. Johns Hopkins Hosp Rep 10:133–196 2. Banfi A, Bonadonna G, Buraggi G et al (1965) Proposta di classificazione e terapia della malattia di Hodgkin. Tumori 51:97–112 3. Easson EC, Russell MH (1963) The cure of Hodgkin’s disease. BMJ 1963:1704–1707 4. Jelliffe AM, Thomson AD (1955) The prognosis in Hodgkin’s disease. Br J Cancer 9:21–36 5. Kaplan HS (1970) On the natural history, treatment and prognosis of Hodgkin’s disease. Harvey lectures 1968–1969. Academic, New York, NY, pp 215–259 6. Musshoff K, Stamm H, Lummel G, Gössel K (1964) Zur prognose der lymphogranulomatose. Klinisches 16. 17. 18. 19. bild un strahlentherapie. Freiburger Krankengut 1938–1958. In: Keiderling W (ed) Beiträge zur Inneren Medizin. FK Schattauer-Verlag, Stuttgart, pp 549–561 Peters MV (1950) A study of survivals in Hodgkin’s disease treated radiologically. Am J Roentgenol 63:299–311 Rosenberg SA (1966) Report of the committee on the staging of Hodgkin’s disease. Cancer Res 26:1310–1310 Carbone PP, Kaplan HS, Musshoff K, Smithers DW, Tubiana M (1971) Report of the committee on Hodgkin’s disease staging classification. Cancer Res 31:1860–1861 Aisenberg AC, Qazi R (1976) Improved survival in Hodgkin’s disease. Cancer 37:2423–2429 Davis S, Dahlberg S, Myers MH, Chen A, Steinhorn SC (1987) Hodgkin's disease in the United States: a comparison of patient characteristics and survival in the centralized cancer patient data system and the surveillance, epidemiology, and end results program. J Natl Cancer Inst 78:471–478 Gobbi PG, Cavalli C, Federico M, Bertoloni D, Di Prisco UA, Rossi A, Silingardi V, Mauri C, Ascari E (1988) Hodgkin’s disease prognosis: a directly predictive equation. Lancet 1:675–679 Hancock BW, Aitken M, Martin JF, Dunsmore IR, Ross CM, Carr I, Emmanuel IG (1979) Hodgkin’s disease in Sheffield (1971–76) (with computer analysis of variables). Clin Oncol 5:283–297 Henry-Amar M, Aeppli DM, Anderson J, Ashley S, Bonichon F, Cox RS, Dahlberg SJ, DeBoer G, Dixon DO, Gobbi PG, Gregory W, Hasenclever D, Löffler M, Pompe Kirn V, Santarelli MT, Specht L, Swindell R, Vaughan Hudson B (1990) Workshop statistical report. In: Somers R, Henry-Amar M, Meerwaldt JH, Carde P (eds) Treatment strategy in Hodgkin’s disease. INSERM/John Libbey Eurotext, London, pp 169–425 Kaplan HS (1973) Survival and relapse rates in Hodgkin’s disease: Stanford experience, 1961–71. Monogr Natl Cancer Inst 36:487–496 Musshoff K, Hartmann C, Niklaus B, Rössnere R (1974) Results of therapy in Hodgkin’s disease: Freiburg i. Br. 1964–1971. In: Musshoff K (ed) Diagnosis and therapy of malignant lymphoma. Springer, Berlin, pp 206–220 Sutcliffe SB, Gospodarowicz MK, Bergsagel DE, Bush RS, Alison RE, Bean HA, Brown TC, Chua T, Clark RM, Curtis JE (1985) Prognostic groups for management of localized Hodgkin’s disease. J Clin Oncol 3:393–401 Noone AM, Howlader N, Krapcho M, Miller D, Brest A, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (2018) SEER cancer statistics review, 1975–2015. National Cancer Institute, Bethesda, MD. https://seer.cancer. gov/csr/1975_2015 Lister TA, Crowther D, Sutcliffe SB, Glatstein E, Canellos GP, Young RC, Rosenberg SA, Coltman 8 Prognostic Factors 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. CA, Tubiana M (1989) Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin’s disease: Cotswolds meeting. J Clin Oncol 7:1630–1636 Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, Lister TA (2014) Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 32:3059–3068 George SL (1988) Identification and assessment of prognostic factors. Semin Oncol 15:462–471 Gospodarowicz MK, O'Sullivan B, Koh ES (2006) Prognostic factors: principles and applications. In: Gospodarowicz MK, O’Sullivan B, Sobin LH (eds) Prognostic factors in cancer, 3rd edn. Wiley-Liss, Hoboken, NJ, pp 23–38 Byar DP (1988) Identification of prognostic factors. In: Buyse ME, Staquet MJ, Sylvester RJ (eds) Cancer clinical trials. Methods and practice. Oxford University Press, Oxford, pp 423–443 Riley RD, Sauerbrei W, Altman DG (2009) Prognostic markers in cancer: the evolution of evidence from single studies to meta-analysis, and beyond. Br J Cancer 100:1219–1229 Byar DP (1991) Problems with using observational databases to compare treatments. Stat Med 10:663–666 Simon R (1984) Importance of prognostic factors in cancer clinical trials. Cancer Treat Rep 68:185–192 Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, Coiffier B, Fisher RI, Hagenbeek A, Zucca E, Rosen ST, Stroobants S, Lister TA, Hoppe RT, Dreyling M, Tobinai K, Vose JM, Connors JM, Federico M, Diehl V (2007) Revised response criteria for malignant lymphoma. J Clin Oncol 25:579–586 Altman DG (2006) Studies investigating prognostic factors: conduct and evaluation. In: Gospodarowicz MK, O’Sullivan B, Sobin LH (eds) Prognostic factors in cancer, 3rd edn. Wiley-Liss, Hoboken, NJ, pp 39–54 Burke HB, Henson DE (1993) The American Joint Committee on Cancer. Criteria for prognostic factors and for an enhanced prognostic system. Cancer 72:3131–3135 Cox DR (1972) Regression models and life-tables. J R Stat Soc B 34:187–220 Simon R (2001) Evaluating prognostic factor studies. In: Gospodarowicz MK, Henson DE, RVP H, O’Sullivan B, Sobin LH, Wittekind C (eds) Prognostic factors in cancer, 2nd edn. Wiley-Liss, New York, NY, pp 49–56 Specht L, Nordentoft AM, Cold S, Clausen NT, Nissen NI (1987) Tumour burden in early stage Hodgkin’s disease: the single most important prognostic factor for outcome after radiotherapy. Br J Cancer 55:535–539 Specht L, Nissen NI (1988) Prognostic factors in Hodgkin’s disease stage IV. Eur J Haematol 41:359–367 161 34. Specht L, Nissen NI (1988) Prognostic factors in Hodgkin’s disease stage III with special reference to tumour burden. Eur J Haematol 41:80–87 35. Specht L, Nissen NI (1988) Hodgkin’s disease stages I and II with infradiaphragmatic presentation: a rare and prognostically unfavourable combination. Eur J Haematol 40:396–402 36. Specht L, Nordentoft AM, Cold S, Clausen NT, Nissen NI (1988) Tumor burden as the most important prognostic factor in early stage Hodgkin’s disease. Relations to other prognostic factors and implications for choice of treatment. Cancer 61:1719–1727 37. Specht L, Nissen NI (1989) Hodgkin's disease and age. Eur J Haematol 43:127–135 38. Specht L, Lauritzen AF, Nordentoft AM, Andersen PK, Christensen BE, Hippe E, Hou-Jensen K, Nissen NI (1990) Tumor cell concentration and tumor burden in relation to histopathologic subtype and other prognostic factors in early stage Hodgkin's disease. The Danish National Hodgkin Study Group. Cancer 65:2594–2601 39. Specht L (1992) Tumour burden as the main indicator of prognosis in Hodgkin’s disease. Eur J Cancer 28A:1982–1985 40. Gobbi PG, Ghirardelli ML, Solcia M, Di Giulio G, Merli F, Tavecchia L, Berte R, Davini O, Levis A, Broglia C, Maffe GC, Ilariucci F, Dore R, Ascari E (2001) Image-aided estimate of tumor burden in Hodgkin’s disease: evidence of its primary prognostic importance. J Clin Oncol 19:1388–1394 41. Gobbi PG, Broglia C, Di Giulio G, Mantelli M, Anselmo P, Merli F, Zinzani PL, Rossi G, Callea V, Iannitto E, Paulli M, Garioni L, Ascari E (2004) The clinical value of tumor burden at diagnosis in Hodgkin lymphoma. Cancer 101:1824–1834 42. Gobbi PG, Valentino F, Bassi E, Coriani C, Merli F, Bonfante V, Marchiano A, Gallamini A, Bolis S, Stelitano C, Levis A, Federico M, Angrilli F, Di GG, Corazza GR (2011) Chemoresistance as a function of the pretherapy tumor burden and the chemotherapy regimen administered: differences observed with 2 current chemotherapy regimens for advanced Hodgkin lymphoma. Clin Lymphoma Myeloma Leuk 11:396–402 43. Gobbi PG, Bergonzi M, Bassi E, Merli F, Coriani C, Stelitano C, Iannitto E, Federico M (2012) Tumor burden in Hodgkin’s lymphoma can be reliably estimated from a few staging parameters. Oncol Rep 28:815–820 44. Gobbi PG, Bassi E, Bergonzi M, Merli F, Coriani C, Iannitto E, Luminari S, Polimeno G, Federico M (2012) Tumour burden predicts treatment resistance in patients with early unfavourable or advanced stage Hodgkin lymphoma treated with ABVD and radiotherapy. Hematol Oncol 30:194–199 45. Gobbi PG, Bergonzi M, Bassi E, Merli F, Coriani C, Federico M (2013) Tumour burden at diagnosis as the main clinical predictor of cell resistance in patients with early stage, favourable Hodgkin lymphoma treated with VBM chemotherapy plus radiotherapy. Hematol Oncol 31:151–155 P. J. Bröckelmann and L. Specht 162 46. Gobbi PG (2014) Tumor burden in Hodgkin's lymphoma: much more than the best prognostic factor. Crit Rev Oncol Hematol 90:17–23 47. Akhtari M, Milgrom SA, Pinnix CC, Reddy JP, Dong W, Smith GL, Mawlawi O, Abou YZ, Gunther J, Osborne EM, Andraos TY, Wogan CF, Rohren E, Garg N, Chuang H, Khoury JD, Oki Y, Fanale M, Dabaja BS (2018) Reclassifying patients with early- stage Hodgkin lymphoma based on functional radiographic markers at presentation. Blood 131:84–94 48. Cottereau AS, Versari A, Loft A, Casasnovas O, Bellei M, Ricci R, Bardet S, Castagnoli A, Brice P, Raemaekers J, Deau B, Fortpied C, Raveloarivahy T, Van ZE, Chartier L, Vander BT, Federico M, Hutchings M, Ricardi U, Andre M, Meignan M (2018) Prognostic value of baseline metabolic tumor volume in early-stage Hodgkin lymphoma in the standard arm of the H10 trial. Blood 131:1456–1463 49. Kanoun S, Rossi C, Berriolo-Riedinger A, Dygai- Cochet I, Cochet A, Humbert O, Toubeau M, Ferrant E, Brunotte F, Casasnovas RO (2014) Baseline metabolic tumour volume is an independent prognostic factor in Hodgkin lymphoma. Eur J Nucl Med Mol Imaging 41:1735–1743 50. Moskowitz AJ, Schoder H, Gavane S, Thoren KL, Fleisher M, Yahalom J, McCall SJ, Cadzin BR, Fox SY, Gerecitano J, Grewal R, Hamlin PA, Horwitz SM, Kumar A, Matasar M, Ni A, Noy A, Palomba ML, Perales MA, Portlock CS, Sauter C, Straus D, Younes A, Zelenetz AD, Moskowitz CH (2017) Prognostic significance of baseline metabolic tumor volume in relapsed and refractory Hodgkin lymphoma. Blood 130:2196–2203 51. Prochazka V, Gawande RS, Cayci Z, Froelich JW, Cao Q, Wilke C, Dusenbery K, Weisdorf DJ, Bachanova V (2018) Positron emission tomography- based assessment of metabolic tumor volume predicts survival after autologous hematopoietic cell transplantation for Hodgkin lymphoma. Biol Blood Marrow Transplant 24:64–70 52. Gallamini A, Kostakoglu L (2017) Metabolic tumor volume: we still need a platinum-standard metric. J Nucl Med 58:196–197 53. Ilyas H, Mikhaeel NG, Dunn JT, Rahman F, Moller H, Smith D, Barrington SF (2018) Defining the optimal method for measuring baseline metabolic tumour volume in diffuse large B cell lymphoma. Eur J Nucl Med Mol Imaging 45:1142–1154 54. Kanoun S, Tal I, Berriolo-Riedinger A, Rossi C, Riedinger JM, Vrigneaud JM, Legrand L, Humbert O, Casasnovas O, Brunotte F, Cochet A (2015) Influence of software tool and methodological aspects of Total metabolic tumor volume calculation on baseline [18F]FDG PET to predict survival in Hodgkin lymphoma. PLoS One 10:e0140830 55. Kostakoglu L, Chauvie S (2018) Metabolic tumor volume metrics in lymphoma. Semin Nucl Med 48:50–66 56. Bonfante V, Santoro A, Viviani S, Zucali R, Devizzi L, Zanini M, Tess JDT, Valagussa P, Banfi A, 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. Bonadonna G (1993) Early stage Hodgkin’s disease: ten-year results of a non-randomised study with radiotherapy alone or combined with MOPP. Eur J Cancer 29A:24–29 Franklin J, Paulus U, Lieberz D, Breuer K, Tesch H, Diehl V (2000) Is the international prognostic score for advanced stage Hodgkin’s disease applicable to early stage patients? German Hodgkin Lymphoma Study Group. Ann Oncol 11:617–623 Glimelius I, Molin D, Amini RM, Gustavsson A, Glimelius B, Enblad G (2003) Bulky disease is the most important prognostic factor in Hodgkin lymphoma stage IIB. Eur J Haematol 71:327–333 Gobbi PG, Gendarini A, Crema A, Cavalli C, Attardo-Parrinello G, Federico M, Di Prisco U, Ascari E (1985) Serum albumin in Hodgkin’s disease. Cancer 55:389–393 Gospodarowicz MK, Sutcliffe SB, Clark RM, Dembo AJ, Fitzpatrick PJ, Munro AJ, Bergsagel DE, Patterson BJ, Tsang R, Chua T (1992) Analysis of supradiaphragmatic clinical stage I and II Hodgkin’s disease treated with radiation alone. Int J Radiat Oncol Biol Phys 22:859–865 Pavlovsky S, Maschio M, Santarelli MT, Muriel FS, Corrado C, Garcia I, Schwartz L, Montero C, Sanahuja FL, Magnasco O (1988) Randomized trial of chemotherapy versus chemotherapy plus radiotherapy for stage I–II Hodgkin’s disease. J Natl Cancer Inst 80:1466–1473 Specht L (1991) Prognostic factors in Hodgkin’s disease. Cancer Treat Rev 18:21–53 Tubiana M, Henry-Amar M, Werf-Messing B, Henry J, Abbatucci J, Burgers M, Hayat M, Somers R, Laugier A, Carde P (1985) A multivariate analysis of prognostic factors in early stage Hodgkin’s disease. Int J Radiat Oncol Biol Phys 11:23–30 Tubiana M, Henry-Amar M, Carde P, Burgers JM, Hayat M, van der Schueren E, Noordijk EM, Tanguy A, Meerwaldt JH, Thomas J (1989) Toward comprehensive management tailored to prognostic factors of patients with clinical stages I and II in Hodgkin’s disease. The EORTC lymphoma group controlled clinical trials: 1964–1987. Blood 73:47–56 Vaughan Hudson B, MacLennan KA, Bennett MH, Easterling MJ, Vaughan Hudson G, Jelliffe AM (1987) Systemic disturbance in Hodgkin’s disease and its relation to histopathology and prognosis (BNLI report no. 30). Clin Radiol 38:257–261 Filippi AR, Botticella A, Bello M, Botto B, Castiglione A, Gavarotti P, Gottardi D, Parvis G, Bisi G, Levis A, Vitolo U, Ricardi U (2013) Interim positron emission tomography and clinical outcome in patients with early stage Hodgkin lymphoma treated with combined modality therapy. Leuk Lymphoma 54:1183–1187 Gallamini A, Kostakoglu L (2012) Interim FDG- PET in Hodgkin lymphoma: a compass for a safe navigation in clinical trials? Blood 120:4913–4920 Hutchings M, Loft A, Hansen M, Pedersen LM, Buhl T, Jurlander J, Buus S, Keiding S, D'Amore 8 Prognostic Factors 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. F, Boesen AM, Berthelsen AK, Specht L (2006) FDG-PET after two cycles of chemotherapy predicts treatment failure and progression-free survival in Hodgkin lymphoma. Blood 107:52–59 Hutchings M, Kostakoglu L, Zaucha JM, Malkowski B, Biggi A, Danielewicz I, Loft A, Specht L, Lamonica D, Czuczman MS, Nanni C, Zinzani PL, Diehl L, Stern R, Coleman M (2014) In vivo treatment sensitivity testing with positron emission tomography/computed tomography after one cycle of chemotherapy for Hodgkin lymphoma. J Clin Oncol 32:2705–2711 Kostakoglu L, Schoder H, Johnson JL, Hall NC, Schwartz LH, Straus DJ, LaCasce AS, Jung SH, Bartlett NL, Canellos GP, Cheson BD (2012) Interim [(18)F]fluorodeoxyglucose positron emission tomography imaging in stage I-II non-bulky Hodgkin lymphoma: would using combined positron emission tomography and computed tomography criteria better predict response than each test alone? Leuk Lymphoma 53:2143–2150 Zinzani PL, Rigacci L, Stefoni V, Broccoli A, Puccini B, Castagnoli A, Vaggelli L, Zanoni L, Argnani L, Baccarani M, Fanti S (2012) Early interim 18F-FDG PET in Hodgkin’s lymphoma: evaluation on 304 patients. Eur J Nucl Med Mol Imaging 39:4–12 Sher DJ, Mauch PM, Van den Abbeele A, LaCasce AS, Czerminski J, Ng AK (2009) Prognostic significance of mid- and post-ABVD PET imaging in Hodgkin’s lymphoma: the importance of involved- field radiotherapy. Ann Oncol 20:1848–1853 Adams HJ, Nievelstein RA, Kwee TC (2015) Prognostic value of interim FDG-PET in Hodgkin lymphoma: systematic review and meta-analysis. Br J Haematol 170:356–366 Adams HJ, Nievelstein RA, Kwee TC (2016) Systematic review and meta-analysis on the prognostic value of complete remission status at FDG- PET in Hodgkin lymphoma after completion of first-line therapy. Ann Hematol 95:1–9 Brockelmann PJ, Angelopoulou MK, Vassilakopoulos TP (2016) Prognostic factors in Hodgkin lymphoma. Semin Hematol 53:155–164 Alonso-Alvarez S, Vidriales MB, Caballero MD, Blanco O, Puig N, Martin A, Penarrubia MJ, Zato E, Galende J, Barez A, Alcoceba M, Orfao A, Gonzalez M, Garcia-Sanz R (2017) The number of tumor infiltrating T-cell subsets in lymph nodes from patients with Hodgkin lymphoma is associated with the outcome after first line ABVD therapy. Leuk Lymphoma 58:1144–1152 Calio A, Zamo A, Ponzoni M, Zanolin ME, Ferreri AJ, Pedron S, Montagna L, Parolini C, Fraifeld VE, Wolfson M, Yanai H, Pizzolo G, Doglioni C, Vinante F, Chilosi M (2015) Cellular senescence markers p16INK4a and p21CIP1/WAF are predictors of Hodgkin lymphoma outcome. Clin Cancer Res 21:5164–5172 Casasnovas RO, Mounier N, Brice P, Divine M, Morschhauser F, Gabarre J, Blay JY, Voillat L, 163 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. Lederlin P, Stamatoullas A, Bienvenu J, Guiguet M, Intrator L, Grandjean M, Briere J, Ferme C, Salles G (2007) Plasma cytokine and soluble receptor signature predicts outcome of patients with classical Hodgkin’s lymphoma: a study from the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 25:1732–1740 Derenzini E, Younes A (2011) Predicting treatment outcome in classical Hodgkin lymphoma: genomic advances. Genome Med 3:26 Diefenbach C, Steidl C (2013) New strategies in Hodgkin lymphoma: better risk profiling and novel treatments. Clin Cancer Res 19:2797–2803 Guo B, Cen H, Tan X, Ke Q (2016) Meta-analysis of the prognostic and clinical value of tumor-associated macrophages in adult classical Hodgkin lymphoma. BMC Med 14:159 Guo X, Wang J, Jin J, Chen H, Zhen Z, Jiang W, Lin T, Huang H, Xia Z, Sun X (2018) High serum level of soluble programmed death ligand 1 is associated with a poor prognosis in Hodgkin lymphoma. Transl Oncol 11:779–785 Hagenbeek A, Gascoyne RD, Dreyling M, Kluin P, Engert A, Salles G (2009) Biomarkers and prognosis in malignant lymphomas. Clin Lymphoma Myeloma 9:160–166 Kanakry JA, Li H, Gellert LL, Lemas MV, Hsieh WS, Hong F, Tan KL, Gascoyne RD, Gordon LI, Fisher RI, Bartlett NL, Stiff P, Cheson BD, Advani R, Miller TP, Kahl BS, Horning SJ, Ambinder RF (2013) Plasma Epstein-Barr virus DNA predicts outcome in advanced Hodgkin lymphoma: correlative analysis from a large north American cooperative group trial. Blood 121:3547–3553 Koh YW, Kang HJ, Park C, Yoon DH, Kim S, Suh C, Go H, Kim JE, Kim CW, Huh J (2012) The ratio of the absolute lymphocyte count to the absolute monocyte count is associated with prognosis in Hodgkin’s lymphoma: correlation with tumor-associated macrophages. Oncologist 17:871–880 Mestre F, Gutierrez A, Ramos R, Martinez-Serra J, Sanchez L, Matheu G, Ros T, Garcia JF, Rodriguez J (2012) Expression of COX-2 on Reed-Sternberg cells is an independent unfavorable prognostic factor in Hodgkin lymphoma treated with ABVD. Blood 119:6072–6079 Navarro A, Munoz C, Gaya A, Diaz-Beya M, Gel B, Tejero R, Diaz T, Martinez A, Monzo M (2013) MiR-SNPs as markers of toxicity and clinical outcome in Hodgkin lymphoma patients. PLoS One 8:e64716 Scott DW, Chan FC, Hong F, Rogic S, Tan KL, Meissner B, Ben-Neriah S, Boyle M, Kridel R, Telenius A, Woolcock BW, Farinha P, Fisher RI, Rimsza LM, Bartlett NL, Cheson BD, Shepherd LE, Advani RH, Connors JM, Kahl BS, Gordon LI, Horning SJ, Steidl C, Gascoyne RD (2013) Gene expression-based model using formalin-fixed paraffin-embedded biopsies predicts overall survival in advanced-stage classical Hodgkin lymphoma. J Clin Oncol 31:692–700 P. J. Bröckelmann and L. Specht 164 89. Steidl C, Lee T, Shah SP, Farinha P, Han G, Nayar T, Delaney A, Jones SJ, Iqbal J, Weisenburger DD, Bast MA, Rosenwald A, Muller-Hermelink HK, Rimsza LM, Campo E, Delabie J, Braziel RM, Cook JR, Tubbs RR, Jaffe ES, Lenz G, Connors JM, Staudt LM, Chan WC, Gascoyne RD (2010) Tumor- associated macrophages and survival in classic Hodgkin’s lymphoma. N Engl J Med 362:875–885 90. Touati M, Delage-Corre M, Monteil J, Abraham J, Moreau S, Remenieras L, Gourin MP, Dmytruk N, Olivrie A, Turlure P, Girault S, Labrousse F, Preux PM, Jaccard A, Bordessoule D (2015) CD68-positive tumor-associated macrophages predict unfavorable treatment outcomes in classical Hodgkin lymphoma in correlation with interim fluorodeoxyglucose- positron emission tomography assessment. Leuk Lymphoma 56:332–341 91. Vassilakopoulos TP, Dimopoulou MN, Angelopoulou MK, Petevi K, Pangalis GA, Moschogiannis M, Dimou M, Boutsikas G, Kanellopoulos A, Gainaru G, Plata E, Flevari P, Koutsi K, Papageorgiou L, Telonis V, Tsaftaridis P, Sachanas S, Yiakoumis X, Tsirkinidis P, Viniou NA, Siakantaris MP, Variami E, Kyrtsonis MC, Meletis J, Panayiotidis P, Konstantopoulos K (2016) Prognostic implication of the absolute lymphocyte to absolute monocyte count ratio in patients with classical Hodgkin lymphoma treated with doxorubicin, bleomycin, vinblastine, and Dacarbazine or equivalent regimens. Oncologist 21:343–353 92. Hasenclever D, Diehl V (1998) A prognostic score for advanced Hodgkin’s disease. International prognostic factors project on advanced Hodgkin’s disease. N Engl J Med 339:1506–1514 93. Canellos GP, Anderson JR, Propert KJ, Nissen N, Cooper MR, Henderson ES, Green MR, Gottlieb A, Peterson BA (1992) Chemotherapy of advanced Hodgkin’s disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med 327:1478–1484 94. Ferme C, Bastion Y, Brice P, Lederlin P, Divine M, Gabarre J, Assouline D, Ferrant A, Berger F, Lepage E (1997) Prognosis of patients with advanced Hodgkin’s disease: evaluation of four prognostic models using 344 patients included in the group d’Etudes des Lymphomes de l’Adulte study. Cancer 80:1124–1133 95. Peterson BA, Pajak TF, Cooper MR, Nissen NI, Glidewell OJ, Holland JF, Bloomfield CD, Gottlieb AJ (1982) Effect of age on therapeutic response and survival in advanced Hodgkin’s disease. Cancer Treat Rep 66:889–898 96. Sjoberg J, Halthur C, Kristinsson SY, Landgren O, Nygell UA, Dickman PW, Bjorkholm M (2012) Progress in Hodgkin lymphoma: a population-based study on patients diagnosed in Sweden from 1973– 2009. Blood 119:990–996 97. Straus DJ, Gaynor JJ, Myers J, Merke DP, Caravelli J, Chapman D, Yahalom J, Clarkson BD (1990) Prognostic factors among 185 adults with newly 98. 99. 100. 101. 102. 103. 104. 105. 106. 107. diagnosed advanced Hodgkin’s disease treated with alternating potentially noncross- resistant chemotherapy and intermediate-dose radiation therapy. J Clin Oncol 8:1173–1186 Proctor SJ, Rueffer JU, Angus B, Breuer K, Flechtner H, Jarrett R, Levis A, Taylor P, Tirelli U (2002) Hodgkin’s disease in the elderly: current status and future directions. Ann Oncol 13(Suppl 1):133–137 Engert A, Ballova V, Haverkamp H, Pfistner B, Josting A, Duhmke E, Muller-Hermelink K, Diehl V (2005) Hodgkin’s lymphoma in elderly patients: a comprehensive retrospective analysis from the German Hodgkin’s study group. J Clin Oncol 23:5052–5060 Boll B, Goergen H, Arndt N, Meissner J, Krause SW, Schnell R, von TB, Eichenauer DA, Sasse S, Fuchs M, Behringer K, Klimm BC, Naumann R, Diehl V, Engert A, Borchmann P (2013) Relapsed hodgkin lymphoma in older patients: a comprehensive analysis from the German Hodgkin Study Group. J Clin Oncol 31:4431–4437 Gobbi PG, Comelli M, Grignani GE, Pieresca C, Bertoloni D, Ascari E (1994) Estimate of expected survival at diagnosis in Hodgkin’s disease: a means of weighting prognostic factors and a tool for treatment choice and clinical research. A report from the international database on Hodgkin’s disease (IDHD). Haematologica 79:241–255 Klimm B, Reineke T, Haverkamp H, Behringer K, Eich HT, Josting A, Pfistner B, Diehl V, Engert A (2005) Role of hematotoxicity and sex in patients with Hodgkin’s lymphoma: an analysis from the German Hodgkin study group. J Clin Oncol 23:8003–8011 Torricelli P, Grimaldi PL, Fiocchi F, Federico M, Romagnoli R (2004) Hodgkin’s disease: a quantitative evaluation by computed tomography of tumor burden. Clin Imaging 28:239–244 Axdorph U, Sjoberg J, Grimfors G, Landgren O, Porwit-MacDonald A, Bjorkholm M (2000) Biological markers may add to prediction of o utcome achieved by the international prognostic score in Hodgkin’s disease. Ann Oncol 11:1405–1411 Nadali G, Vinante F, Ambrosetti A, Todeschini G, Veneri D, Zanotti R, Meneghini V, Ricetti MM, Benedetti F, Vassanelli A (1994) Serum levels of soluble CD30 are elevated in the majority of untreated patients with Hodgkin’s disease and correlate with clinical features and prognosis. J Clin Oncol 12:793–797 Zanotti R, Trolese A, Ambrosetti A, Nadali G, Visco C, Ricetti MM, Benedetti F, Pizzolo G (2002) Serum levels of soluble CD30 improve international prognostic score in predicting the outcome of advanced Hodgkin’s lymphoma. Ann Oncol 13:1908–1914 Sauer M, Plutschow A, Jachimowicz RD, Kleefisch D, Reiners KS, Ponader S, Engert A, von Strandmann EP (2013) Baseline serum TARC levels predict therapy outcome in patients with Hodgkin lymphoma. Am J Hematol 88:113–115 8 Prognostic Factors 108. Sureda A, Connors JM, Younes A, Gallamini A, Ansell SM, Kim WS, Miall F, Bajel A, Knopinska- Posluszny W, Ogden CA, Kuroda S, Liu R, Trepicchio WL, Radford J (2018) Serum sCD30 and TARC do not correlate with PETZ-based response assessment in patients (pts) with stage III or IV classical Hodgkin lymphoma (cHL). HemaSphere 2:35–36 109. Bohlen H, Kessler M, Sextro M, Diehl V, Tesch H (2000) Poor clinical outcome of patients with Hodgkin’s disease and elevated interleukin-10 serum levels. Clinical significance of interleukin-10 serum levels for Hodgkin’s disease. Ann Hematol 79:110–113 110. Marri PR, Hodge LS, Maurer MJ, Ziesmer SC, Slager SL, Habermann TM, Link BK, Cerhan JR, Novak AJ, Ansell SM (2013) Prognostic significance of pretreatment serum cytokines in classical Hodgkin lymphoma. Clin Cancer Res 19:6812–6819 111. Vassilakopoulos TP, Nadali G, Angelopoulou MK, Siakantaris MP, Dimopoulou MN, Kontopidou FN, Karkantaris C, Kokoris SI, Kyrtsonis MC, Tsaftaridis P, Pizzolo G, Pangalis GA (2002) The prognostic significance of beta(2)-microglobulin in patients with Hodgkin’s lymphoma. Haematologica 87:701–708 112. Meador CB, Lovly CM (2015) Liquid biopsies reveal the dynamic nature of resistance mechanisms in solid tumors. Nat Med 21:663–665 113. Vandenberghe P, Wlodarska I, Tousseyn T, Dehaspe L, Dierickx D, Verheecke M, Uyttebroeck A, Bechter O, Delforge M, Vandecaveye V, Brison N, Verhoef GE, Legius E, Amant F, Vermeesch JR (2015) Non-invasive detection of genomic imbalances in Hodgkin/Reed-Sternberg cells in early and advanced stage Hodgkin’s lymphoma by sequencing of circulating cell-free DNA: a technical proof-of- principle study. Lancet Haematol 2:e55–e65 114. Bräuninger A, Desch A-K, Kunze K, Boten A, Brobeil A, Rummel M, Kurch L, Georgi T, Kluge R, Mauz-Körholz C, Körholz D, Gattenlöhner S (2018) Genotyping circulating tumor DNA of pediatric Hodgkin lymphoma patients to determine pathogenic mechanisms and monitor therapy. HemaSphere 2:4–4 115. Jin MC, Kurtz DM, Esfahani MS, Sworder BJ, Schroer-Martin J, Soo J, Glover C, Roschewski M, Wilson W, Düehrsen U, Hüttmann A, Rossi D, Gaidano G, Westin J, Diehn M, Advani R, Alizadeh AA (2018) Circulating tumor DNA as a biomarker for the noninvasive genotyping and monitoring of classical Hodgkin lymphoma. HemaSphere 2:4–5 116. Tan KL, Scott DW, Hong F, Kahl BS, Fisher RI, Bartlett NL, Advani RH, Buckstein R, Rimsza LM, Connors JM, Steidl C, Gordon LI, Horning SJ, Gascoyne RD (2012) Tumor-associated macrophages predict inferior outcomes in classic Hodgkin lymphoma: a correlative study from the E2496 intergroup trial. Blood 120:3280–3287 165 117. Roemer MG, Advani RH, Ligon AH, Natkunam Y, Redd RA, Homer H, Connelly CF, Sun HH, Daadi SE, Freeman GJ, Armand P, Chapuy B et al (2016) PD-L1 and PD-L2 genetic alterations define classical Hodgkin lymphoma and predict outcome. J Clin Oncol 34:2690–2697 118. Gallamini A, Rigacci L, Merli F, Nassi L, Bosi A, Capodanno I, Luminari S, Vitolo U, Sancetta R, Iannitto E, Trentin L, Stelitano C, Tavera S, Biggi A, Castagnoli A, Versari A, Gregianin M, Pelosi E, Torchio P, Levis A (2006) The predictive value of positron emission tomography scanning performed after two courses of standard therapy on treatment outcome in advanced stage Hodgkin's disease. Haematologica 91:475–481 119. Hutchings M, Mikhaeel NG, Fields PA, Nunan T, Timothy AR (2005) Prognostic value of interim FDG-PET after two or three cycles of chemotherapy in Hodgkin lymphoma. Ann Oncol 16:1160–1168 120. Zinzani PL, Tani M, Fanti S, Alinari L, Musuraca G, Marchi E, Stefoni V, Castellucci P, Fina M, Farshad M, Pileri S, Baccarani M (2006) Early positron emission tomography (PET) restaging: a predictive final response in Hodgkin’s disease patients. Ann Oncol 17:1296–1300 121. Gallamini A, Hutchings M, Rigacci L, Specht L, Merli F, Hansen M, Patti C, Loft A, Di Raimondo F, D'Amore F, Biggi A, Vitolo U, Stelitano C, Sancetta R, Trentin L, Luminari S, Iannitto E, Viviani S, Pierri I, Levis A (2007) Early interim 2-[18F]fluoro- 2- deoxy-D-glucose positron emission tomography is prognostically superior to international prognostic score in advanced-stage Hodgkin’s lymphoma: a report from a joint Italian-Danish study. J Clin Oncol 25:3746–3752 122. Johnson P, Federico M, Kirkwood A, Fossa A, Berkahn L, Carella A, D'Amore F, Enblad G, Franceschetto A, Fulham M, Luminari S, O'Doherty M, Patrick P, Roberts T, Sidra G, Stevens L, Smith P, Trotman J, Viney Z, Radford J, Barrington S (2016) Adapted treatment guided by interim PET-CT scan in advanced Hodgkin’s lymphoma. N Engl J Med 374:2419–2429 123. Borchmann P, Goergen H, Kobe C, Lohri A, Greil R, Eichenauer DA, Zijlstra JM, Markova J, Meissner J, Feuring-Buske M, Huttmann A, Dierlamm J, Soekler M, Beck HJ, Willenbacher W, Ludwig WD, Pabst T, Topp MS, Hitz F, Bentz M, Keller UB, Kuhnhardt D, Ostermann H, Schmitz N, Hertenstein B, Aulitzky W, Maschmeyer G, Vieler T, Eich H, Baues C, Stein H, Fuchs M, Kuhnert G, Diehl V, Dietlein M, Engert A (2018) PET-guided treatment in patients with advanced-stage Hodgkin’s lymphoma (HD18): final results of an open-label, international, randomised phase 3 trial by the German Hodgkin Study Group. Lancet 390:2790–2802 124. Casanovas O, Brice P, Bouabdallah R, Salles G, Stamatoullas A, Dupuis J, Reman O, Gastinne T, Joly B, Bouabdallah K, Nicolas-Virelizier E, Feugier P, Morschhauser F, Delarue R, Berriolo-Riedinger A, P. J. Bröckelmann and L. Specht 166 125. 126. 127. 128. 129. 130. 131. Edeline V, Traverse-Giehen A, Andre M, Mounier N, Meignan M (2018) Final analysis of the AHL2011 randomized phase III LYSA study comparing an early PET driven treatment de-escalation to a not PET-monitored strategy in patients with advanced stages Hodgkin lymphoma. EHA Learning Center, The Hague. https://learningcenter.ehaweb.org/ eha/2018/stockholm/214504/olivier.casasnovas. final.analysis.of.the.ahl2011.randomized.phase.iii. lysa.html?f=topic=1574∗media=3 Barrington SF, Kirkwood AA, Franceschetto A, Fulham MJ, Roberts TH, Almquist H, Brun E, Hjorthaug K, Viney ZN, Pike LC, Federico M, Luminari S, Radford J, Trotman J, Fossa A, Berkahn L, Molin D, D'Amore F, Sinclair DA, Smith P, O'Doherty MJ, Stevens L, Johnson PW (2016) PET-CT for staging and early response: results from the response-adapted therapy in advanced Hodgkin lymphoma study. Blood 127:1531–1538 Diehl V, Franklin J, Pfreundschuh M, Lathan B, Paulus U, Hasenclever D, Tesch H, Herrmann R, Dorken B, Muller-Hermelink HK, Duhmke E, Loeffler M (2003) Standard and increased-dose BEACOPP chemotherapy compared with COPP- ABVD for advanced Hodgkin’s disease. N Engl J Med 348:2386–2395 Duggan DB, Petroni GR, Johnson JL, Glick JH, Fisher RI, Connors JM, Canellos GP, Peterson BA (2003) Randomized comparison of ABVD and MOPP/ABV hybrid for the treatment of advanced Hodgkin’s disease: report of an intergroup trial. J Clin Oncol 21:607–614 Gobbi PG, Zinzani PL, Broglia C, Comelli M, Magagnoli M, Federico M, Merli F, Iannitto E, Tura S, Ascari E (2001) Comparison of prognostic models in patients with advanced Hodgkin disease. Promising results from integration of the best three systems. Cancer 91:1467–1478 Johnson PW, Radford JA, Cullen MH, Sydes MR, Walewski J, Jack AS, MacLennan KA, Stenning SP, Clawson S, Smith P, Ryder D, Hancock BW (2005) Comparison of ABVD and alternating or hybrid multidrug regimens for the treatment of advanced Hodgkin's lymphoma: results of the United Kingdom lymphoma group LY09 trial (ISRCTN97144519). J Clin Oncol 23:9208–9218 Moccia AA, Donaldson J, Chhanabhai M, Hoskins PJ, Klasa RJ, Savage KJ, Shenkier TN, Slack GW, Skinnider B, Gascoyne RD, Connors JM, Sehn LH (2012) International prognostic score in advanced- stage Hodgkin’s lymphoma: altered utility in the modern era. J Clin Oncol 30:3383–3388 Radford JA, Rohatiner AZ, Ryder WD, Deakin DP, Barbui T, Lucie NP, Rossi A, Dunlop DJ, Cowan RA, Wilkinson PM, Gupta RK, James RD, Shamash J, Chang J, Crowther D, Lister TA (2002) ChlVPP/ EVA hybrid versus the weekly VAPEC-B regimen for previously untreated Hodgkin’s disease. J Clin Oncol 20:2988–2994 132. Diefenbach CS, Li H, Hong F, Gordon LI, Fisher RI, Bartlett NL, Crump M, Gascoyne RD, Wagner H Jr, Stiff PJ, Cheson BD, Stewart DA, Kahl BS, Friedberg JW, Blum KA, Habermann TM, Tuscano JM, Hoppe RT, Horning SJ, Advani RH (2015) Evaluation of the international prognostic score (IPS-7) and a simpler prognostic score (IPS-3) for advanced Hodgkin lymphoma in the modern era. Br J Haematol 171:530–538 133. Bierman PJ, Lynch JC, Bociek RG, Whalen VL, Kessinger A, Vose JM, Armitage JO (2002) The international prognostic factors project score for advanced Hodgkin’s disease is useful for predicting outcome of autologous hematopoietic stem cell transplantation. Ann Oncol 13:1370–1377 134. Gisselbrecht C, Mounier N, Andre M, Casanovas O, Reman O, Sebban C, Divine M, Brice P, Briere J, Hennequin C, Ferme C (2005) How to define intermediate stage in Hodgkin’s lymphoma? Eur J Haematol Suppl 75:111–114 135. Bonfante V, Santoro A, Viviani S, Devizzi L, Balzarotti M, Soncini F, Zanini M, Valagussa P, Bonadonna G (1997) Outcome of patients with Hodgkin’s disease failing after primary MOPP- ABVD. J Clin Oncol 15:528–534 136. Brice P, Bastion Y, Divine M, Nedellec G, Ferrant A, Gabarre J, Reman O, Lepage E, Ferme C (1996) Analysis of prognostic factors after the first relapse of Hodgkin’s disease in 187 patients. Cancer 78:1293–1299 137. Ferme C, Bastion Y, Lepage E, Berger F, Brice P, Morel P, Gabarre J, Nedellec G, Reman O, Cheron N (1995) The MINE regimen as intensive salvage chemotherapy for relapsed and refractory Hodgkin’s disease. Ann Oncol 6:543–549 138. Lohri A, Barnett M, Fairey RN, O'Reilly SE, Phillips GL, Reece D, Voss N, Connors JM (1991) Outcome of treatment of first relapse of Hodgkin’s disease after primary chemotherapy: identification of risk factors from the British Columbia experience 1970 to 1988. Blood 77:2292–2298 139. Longo DL, Duffey PL, Young RC, Hubbard SM, Ihde DC, Glatstein E, Phares JC, Jaffe ES, Urba WJ, DeVita VT Jr (1992) Conventional-dose salvage combination chemotherapy in patients relapsing with Hodgkin’s disease after combination chemotherapy: the low probability for cure. J Clin Oncol 10:210–218 140. Viviani S, Santoro A, Negretti E, Bonfante V, Valagussa P, Bonadonna G (1990) Salvage chemotherapy in Hodgkin’s disease. Results in patients relapsing more than twelve months after first complete remission. Ann Oncol 1:123–127 141. Josting A, Franklin J, May M, Koch P, Beykirch MK, Heinz J, Rudolph C, Diehl V, Engert A (2001) New prognostic score based on treatment outcome of patients with relapsed Hodgkin’s lymphoma registered in the database of the German Hodgkin’s Lymphoma Study Group. J Clin Oncol 20:221–230 8 Prognostic Factors 142. Hagemeister FB, Tannir N, McLaughlin P, Salvador P, Riggs S, Velasquez WS, Cabanillas F (1987) MIME chemotherapy (methyl-GAG, ifosfamide, methotrexate, etoposide) as treatment for recurrent Hodgkin’s disease. J Clin Oncol 5:556–561 143. Perren TJ, Selby PJ, Milan S, Meldrum M, McElwain TJ (1990) Etoposide and adriamycin containing combination chemotherapy (HOPE-Bleo) for relapsed Hodgkin’s disease. Br J Cancer 61:919–923 144. Straus DJ, Myers J, Koziner B, Lee BJ, Clarkson BD (1983) Combination chemotherapy for the treatment of Hodgkin’s disease in relapse. Results with lomustine (CCNU), melphalan (Alkeran), and vindesine (DVA) alone (CAD) and in alternation with MOPP and doxorubicin (Adriamycin), bleomycin, and vinblastine (ABV). Cancer Chemother Pharmacol 11:80–85 145. Josting A, Schmitz N (2004) Insights into 25 years of clinical trials of the GHSG: Relapsed and refractory Hodgkin’s disease. In: Diehl V, Josting A (eds) 25 years German Hodgkin Study Group. Urban & Vogel, Munich, pp 89–99 146. Salvagno L, Soraru M, Aversa SM, Bianco A, Chiarion S, Pappagallo GL, Fiorentino MV (1993) Late relapses in Hodgkin’s disease: outcome of patients relapsing more than twelve months after primary chemotherapy. Ann Oncol 4:657–662 147. Brada M, Eeles R, Ashley S, Nichols J, Horwich A (1992) Salvage radiotherapy in recurrent Hodgkin’s disease. Ann Oncol 3:131–135 148. Josting A, Nogova L, Franklin J, Glossmann JP, Eich HT, Sieber M, Schober T, Boettcher HD, Schulz U, Muller RP, Diehl V, Engert A (2005) Salvage radiotherapy in patients with relapsed and refractory Hodgkin’s lymphoma: a retrospective analysis from the German Hodgkin lymphoma study group. J Clin Oncol 23:1522–1529 149. Leigh BR, Fox KA, Mack CF, Baier M, Miller TP, Cassady JR (1993) Radiation therapy salvage of Hodgkin’s disease following chemotherapy failure. Int J Radiat Oncol Biol Phys 27:855–862 150. Roach M III, Kapp DS, Rosenberg SA, Hoppe RT (1987) Radiotherapy with curative intent: an option in selected patients relapsing after chemotherapy for advanced Hodgkin’s disease. J Clin Oncol 5:550–555 151. Wirth A, Corry J, Laidlaw C, Matthews J, Liew KH (1997) Salvage radiotherapy for Hodgkin’s disease following chemotherapy failure. Int J Radiat Oncol Biol Phys 39:599–607 152. Linch DC, Winfield D, Goldstone AH, Moir D, Hancock B, McMillan A, Chopra R, Milligan D, Hudson GV (1993) Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin’s disease: results of a BNLI randomised trial. Lancet 341:1051–1054 153. Schmitz N, Pfistner B, Sextro M, Sieber M, Carella AM, Haenel M, Boissevain F, Zschaber R, Muller P, Kirchner H, Lohri A, Decker S, Koch B, Hasenclever 167 154. 155. 156. 157. 158. 159. 160. D, Goldstone AH, Diehl V (2002) Aggressive conventional chemotherapy compared with high- dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin’s disease: a randomised trial. Lancet 359:2065–2071 Argiris A, Seropian S, Cooper DL (2000) High-dose BEAM chemotherapy with autologous peripheral blood progenitor-cell transplantation for unselected patients with primary refractory or relapsed Hodgkin’s disease. Ann Oncol 11:665–672 Bierman PJ, Anderson JR, Freeman MB, Vose JM, Kessinger A, Bishop MR, Armitage JO (1996) High-dose chemotherapy followed by autologous hematopoietic rescue for Hodgkin’s disease patients following first relapse after chemotherapy. Ann Oncol 7:151–156 Czyz A, Lojko-Dankowska A, Dytfeld D, Nowicki A, Gil L, Matuszak M, Kozlowska-Skrzypczak M, Kazmierczak M, Bembnista E, Komarnicki M (2013) Prognostic factors and long-term outcome of autologous haematopoietic stem cell transplantation following a uniform-modified BEAM-conditioning regimen for patients with refractory or relapsed Hodgkin lymphoma: a single-center experience. Med Oncol 30:611 Ferme C, Mounier N, Divine M, Brice P, Stamatoullas A, Reman O, Voillat L, Jaubert J, Lederlin P, Colin P, Berger F, Salles G (2002) Intensive salvage therapy with high-dose chemotherapy for patients with advanced Hodgkin’s disease in relapse or failure after initial chemotherapy: results of the Groupe d’Etudes des Lymphomes de l’Adulte H89 trial. J Clin Oncol 20:467–475 Fernandez de Larrea C, Martinez C, Gaya A, Lopez-Guillermo A, Rovira M, Fernandez-Aviles F, Lozano M, Bosch F, Esteve J, Nomdedeu B, Montserrat E, Carreras E (2010) Salvage chemotherapy with alternating MINE-ESHAP regimen in relapsed or refractory Hodgkin’s lymphoma followed by autologous stem-cell transplantation. Ann Oncol 21:1211–1216 Hahn T, Benekli M, Wong C, Moysich KB, Hyland A, Michalek AM, Alam A, Baer MR, Bambach B, Czuczman MS, Wetzler M, Becker JL, McCarthy PL (2005) A prognostic model for prolonged event- free survival after autologous or allogeneic blood or marrow transplantation for relapsed and refractory Hodgkin’s disease. Bone Marrow Transplant 35:557–566 Sureda A, Constans M, Iriondo A, Arranz R, Caballero MD, Vidal MJ, Petit J, Lopez A, Lahuerta JJ, Carreras E, Garcia-Conde J, Garcia-Larana J, Cabrera R, Jarque I, Carrera D, Garcia-Ruiz JC, Pascual MJ, Rifon J, Moraleda JM, Perez-Equiza K, Albo C, Diaz-Mediavilla J, Torres A, Torres P, Besalduch J, Marin J, Mateos MV, Fernandez- Ranada JM, Sierra J, Conde E (2005) Prognostic factors affecting long-term outcome after stem cell P. J. Bröckelmann and L. Specht 168 161. 162. 163. 164. 165. 166. 167. 168. transplantation in Hodgkin’s lymphoma autografted after a first relapse. Ann Oncol 16:625–633 Viviani S, Di NM, Bonfante V, Di SA, Carlo-Stella C, Matteucci P, Magni M, Devizzi L, Valagussa P, Gianni AM (2010) Long-term results of high-dose chemotherapy with autologous bone marrow or peripheral stem cell transplant as first salvage treatment for relapsed or refractory Hodgkin lymphoma: a single institution experience. Leuk Lymphoma 51:1251–1259 Jabbour E, Hosing C, Ayers G, Nunez R, Anderlini P, Pro B, Khouri I, Younes A, Hagemeister F, Kwak L, Fayad L (2007) Pretransplant positive positron emission tomography/gallium scans predict poor outcome in patients with recurrent/refractory Hodgkin lymphoma. Cancer 109:2481–2489 Mocikova H, Pytlik R, Markova J, Steinerova K, Kral Z, Belada D, Trnkova M, Trneny M, Koza V, Mayer J, Zak P, Kozak T (2011) Pre-transplant positron emission tomography in patients with relapsed Hodgkin lymphoma. Leuk Lymphoma 52:1668–1674 Moskowitz AJ, Yahalom J, Kewalramani T, Maragulia JC, Vanak JM, Zelenetz AD, Moskowitz CH (2010) Pretransplantation functional imaging predicts outcome following autologous stem cell transplantation for relapsed and refractory Hodgkin lymphoma. Blood 116:4934–4937 Moskowitz CH, Yahalom J, Zelenetz AD, Zhang Z, Filippa D, Teruya-Feldstein J, Kewalramani T, Moskowitz AJ, Rice RD, Maragulia J, Vanak J, Trippett T, Hamlin P, Horowitz S, Noy A, O'Connor OA, Portlock C, Straus D, Nimer SD (2010) High- dose chemo-radiotherapy for relapsed or refractory Hodgkin lymphoma and the significance of pre-transplant functional imaging. Br J Haematol 148:890–897 Moskowitz CH, Matasar MJ, Zelenetz AD, Nimer SD, Gerecitano J, Hamlin P, Horwitz S, Moskowitz AJ, Noy A, Palomba L, Perales MA, Portlock C, Straus D, Maragulia JC, Schoder H, Yahalom J (2012) Normalization of pre-ASCT, FDG-PET imaging with second-line, non-cross-resistant, chemotherapy programs improves event-free survival in patients with Hodgkin lymphoma. Blood 119:1665–1670 Sucak GT, Ozkurt ZN, Suyani E, Yasar DG, Akdemir OU, Aki Z, Yegin ZA, Yagci M, Kapucu OL (2011) Early post-transplantation positron emission tomography in patients with Hodgkin lymphoma is an independent prognostic factor with an impact on overall survival. Ann Hematol 90:1329–1336 Popat U, Hosing C, Saliba RM, Anderlini P, van Besien K, Przepiorka D, Khouri IF, Gajewski J, Claxton D, Giralt S, Rodriguez M, Romaguera J, Hagemeister F, Ha C, Cox J, Cabanillas F, Andersson BS, Champlin RE (2004) Prognostic factors for disease progression after high-dose chemotherapy and autologous hematopoietic stem cell transplantation 169. 170. 171. 172. 173. 174. 175. 176. for recurrent or refractory Hodgkin’s lymphoma. Bone Marrow Transplant 33:1015–1023 Josting A, Rudolph C, Mapara M, Glossmann JP, Sienawski M, Sieber M, Kirchner HH, Dorken B, Hossfeld DK, Kisro J, Metzner B, Berdel WE, Diehl V, Engert A (2005) Cologne high-dose sequential chemotherapy in relapsed and refractory Hodgkin lymphoma: results of a large multicenter study of the German Hodgkin lymphoma study group (GHSG). Ann Oncol 16:116–123 Lumley MA, Milligan DW, Knechtli CJ, Long SG, Billingham LJ, McDonald DF (1996) High lactate dehydrogenase level is associated with an adverse outlook in autografting for Hodgkin’s disease. Bone Marrow Transplant 17:383–388 Brockelmann PJ, Muller H, Casasnovas O, Hutchings M, von Tresckow B, Jurgens M, McCall SJ, Morschhauser F, Fuchs M, Borchmann P, Moskowitz CH, Engert A (2017) Risk factors and a prognostic score for survival after autologous stem-cell transplantation for relapsed or refractory Hodgkin lymphoma. Ann Oncol 28:1352–1358 Bierman PJ, Bagin RG, Jagannath S, Vose JM, Spitzer G, Kessinger A, Dicke KA, Armitage JO (1993) High dose chemotherapy followed by autologous hematopoietic rescue in Hodgkin’s disease: long-term follow-up in 128 patients. Ann Oncol 4:767–773 Brice P, Bouabdallah R, Moreau P, Divine M, Andre M, Aoudjane M, Fleury J, Anglaret B, Baruchel A, Sensebe L, Colombat P (1997) Prognostic factors for survival after high-dose therapy and autologous stem cell transplantation for patients with relapsing Hodgkin’s disease: analysis of 280 patients from the French registry. Societe Francaise de Greffe de Moelle. Bone Marrow Transplant 20:21–26 Chopra R, McMillan AK, Linch DC, Yuklea S, Taghipour G, Pearce R, Patterson KG, Goldstone AH (1993) The place of high-dose BEAM therapy and autologous bone marrow transplantation in poor-risk Hodgkin's disease. A single-center eight- year study of 155 patients. Blood 81:1137–1145 Horning SJ, Chao NJ, Negrin RS, Hoppe RT, Long GD, Hu WW, Wong RM, Brown BW, Blume KG (1997) High-dose therapy and autologous hematopoietic progenitor cell transplantation for recurrent or refractory Hodgkin’s disease: analysis of the Stanford University results and prognostic indices. Blood 89:801–813 Wheeler C, Eickhoff C, Elias A, Ibrahim J, Ayash L, McCauley M, Mauch P, Schwartz G, Eder JP, Mazanet R, Ferrara J, Rimm IJ, Guinan E, Bierer B, Gilliland G, Churchill WH, Ault K, Parsons S, Antman K, Schnipper L, Tepler I, Gaynes L, Frei E III, Kadin M, Antin J (1997) High-dose cyclophosphamide, carmustine, and etoposide with autologous transplantation in Hodgkin's disease: a prognostic model for treatment outcomes. Biol Blood Marrow Transplant 3:98–106 8 Prognostic Factors 177. Williams CD, Goldstone AH, Pearce R, Green S, Armitage JO, Carella A, Meloni G (1993) Autologous bone marrow transplantation for pediatric Hodgkin’s disease: a case-matched comparison with adult patients by the European bone marrow transplant group lymphoma registry. J Clin Oncol 11:2243–2249 178. Sirohi B, Cunningham D, Powles R, Murphy F, Arkenau T, Norman A, Oates J, Wotherspoon A, Horwich A (2008) Long-term outcome of autologous stem-cell transplantation in relapsed or refractory Hodgkin’s lymphoma. Ann Oncol 19:1312–1319 179. Arai S, Fanale M, DeVos S, Engert A, Illidge T, Borchmann P, Younes A, Morschhauser F, McMillan A, Horning SJ (2013) Defining a Hodgkin lymphoma population for novel therapeutics after relapse from autologous hematopoietic cell transplant. Leuk Lymphoma 54:2531–2533 180. Kaloyannidis P, Voutiadou G, Baltadakis I, Tsirigotis P, Spyridonidis A, Repousis P, Balta A, Tsimberis S, Karakasis D, Sakellari I, Dervenoulas I, Harhalakis N, Anagnostopoulos A (2012) Outcomes of Hodgkin’s lymphoma patients with relapse or progression following autologous hematopoietic cell transplantation. Biol Blood Marrow Transplant 18:451–457 181. Moskowitz AJ, Perales MA, Kewalramani T, Yahalom J, Castro-Malaspina H, Zhang Z, Vanak J, Zelenetz AD, Moskowitz CH (2009) Outcomes for patients who fail high dose chemoradiotherapy and autologous stem cell rescue for relapsed and primary refractory Hodgkin lymphoma. Br J Haematol 146:158–163 182. von Tresckow B, Muller H, Eichenauer DA, Glossmann JP, Josting A, Boll B, Klimm B, Sasse S, Fuchs M, Borchmann P, Engert A (2014) Outcome and risk factors of patients with Hodgkin lymphoma who relapse or progress after autologous stem cell transplant. Leuk Lymphoma 55:1922–1924 183. Josting A, Franklin J, May M, Koch P, Beykirch MK, Heinz J, Rudolph C, Diehl V, Engert A (2002) New prognostic score based on treatment outcome of patients with relapsed Hodgkin’s lymphoma registered in the database of the German Hodgkin’s lymphoma study group. J Clin Oncol 20:221–230 184. Josting A, Muller H, Borchmann P, Baars JW, Metzner B, Dohner H, Aurer I, Smardova L, Fischer T, Niederwieser D, Schafer-Eckart K, Schmitz N, Sureda A, Glossmann J, Diehl V, DeJong D, Hansmann ML, Raemaekers J, Engert A (2010) Dose 169 185. 186. 187. 188. 189. 190. intensity of chemotherapy in patients with relapsed Hodgkin’s lymphoma. J Clin Oncol 28:5074–5080 Hahn T, McCarthy PL, Carreras J, Zhang MJ, Lazarus HM, Laport GG, Montoto S, Hari PN (2013) Simplified validated prognostic model for progression-free survival after autologous transplantation for Hodgkin lymphoma. Biol Blood Marrow Transplant 19:1740–1744 Younes A, Gopal AK, Smith SE, Ansell SM, Rosenblatt JD, Savage KJ, Ramchandren R, Bartlett NL, Cheson BD et al (2012) Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol 30:2183–2189 Moskowitz CH, Walewski J, Nademanee A, Masszi T, Agura E, Holowiecki J, Abidi MH, Chen AI, Stiff P, Viviani S, Bachanova V, Sureda A, McClendon T, Lee C, Lisano J, Sweetenham J (2018) Five-year PFS from the AETHERA trial of brentuximab vedotin for Hodgkin lymphoma at high risk of progression or relapse. Blood 132(25):2639–2642 Chen R, Zinzani PL, Fanale MA, Armand P, Johnson NA, Brice P, Radford J, Ribrag V, Molin D, Vassilakopoulos TP, Tomita A, von Tresckow B, Shipp MA, Zhang Y, Ricart AD, Balakumaran A, Moskowitz CH (2017) Phase II study of the efficacy and safety of Pembrolizumab for relapsed/ refractory classic Hodgkin lymphoma. J Clin Oncol 35:2125–2132 Younes A, Santoro A, Shipp M, Zinzani PL, Timmerman JM, Ansell S, Armand P, Fanale M, Ratanatharathorn V, Kuruvilla J, Cohen JB, Collins G, Savage KJ, Trneny M, Kato K, Farsaci B, Parker SM, Rodig S, Roemer MG, Ligon AH, Engert A (2016) Nivolumab for classical Hodgkin’s lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol 17:1283–1294 MGM R, Redd RA, Cader FZ, Pak CJ, Abdelrahman S, Ouyang J, Sasse S, Younes A, Fanale M, Santoro A, Zinzani PL, Timmerman J, Collins GP, Ramchandren R, Cohen JB, de Boer JP, Kuruvilla J, Savage KJ, Trneny M, Ansell S, Kato K, Farsaci B, Sumbul A, Armand P, Neuberg DS, Pinkus GS, Ligon AH, Rodig SJ, Shipp MA (2018) Major histocompatibility complex class II and programmed death ligand 1 expression predict outcome after programmed death 1 blockade in classic Hodgkin lymphoma. J Clin Oncol 36:942–950 9 Principles of Radiation Therapy for Hodgkin Lymphoma Joachim Yahalom, Bradford S. Hoppe, Joanna C. Yang, and Richard T. Hoppe Contents 9.1 Principles of Radiation Therapy of Hodgkin Lymphoma 173 9.2 The Evolution of Radiotherapy for HL 173 9.3 9.3.1 9.3.2 9.3.3 9.3.4 Indications for Radiation Therapy in HL Lymphocyte-Predominant HL Classic Hodgkin: Stage I–II Stage III–IV HL RT in Salvage Programs for Refractory and Relapsed HL 174 174 174 177 178 Radiation Fields and Volumes: Principles and Design Extended-Field Radiation Therapy Involved-Field Radiation Therapy Involved-Site Radiation Therapy (ISRT): The New Standard Volume for HL 9.4.3.1 ISRT When RT Is the Primary Treatment 9.4.3.2 ISRT When RT Is Part of Combined-Modality Treatment 9.4.4 Involved-Node Radiation Therapy (INRT): A Special Case of ISRT 9.4.5 Volume Definitions for Planning ISRT and INRT 9.4.5.1 Volume of Interest Acquisition 179 179 179 9.4 9.4.1 9.4.2 9.4.3 180 180 180 181 182 182 J. Yahalom (*) Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA e-mail: yahalomj@mskcc.org B. S. Hoppe Department of Radiation Oncology, Mayo Clinic Florida, Jacksonville, FL, USA e-mail: hoppe.bradford@mayo.edu J. C. Yang Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA e-mail: joanna.yang@ucsf.edu R. T. Hoppe Department of Radiation Oncology, Stanford University Medical Center, Stanford, CA, USA e-mail: rhoppe@stanford.edu © Springer Nature Switzerland AG 2020 A. Engert, A. Younes (eds.), Hodgkin Lymphoma, Hematologic Malignancies, https://doi.org/10.1007/978-3-030-32482-7_9 171 J. Yahalom et al. 172 9.4.5.2 9.4.5.3 9.4.5.4 9.4.5.5 9.4.6 9.4.6.1 9.4.6.2 9.4.6.3 9.4.6.4 9.4.7 etermination of Gross Tumor Volume (GTV) D Determination of Clinical Target Volume (CTV) Determination of Internal Target Volume (ITV) Determination of Planning Target Volume (PTV) Determination of Organs at Risk (OAR) Lung Heart Thyroid Second Cancers Consolidation Volume Radiation Therapy (CVRT) 182 182 182 182 183 183 183 184 184 184 9.5 9.5.1 9.5.2 ose Considerations and Recommendations D The Significance of Reducing the Radiation Dose Dose Recommendations 184 185 186 9.6 9.6.1 9.6.2 ew Aspects of Radiation Volume Definition and Treatment Delivery N New Technologies Deep Inspiration Breath Hold 186 187 187 9.7 Proton Therapy 192 9.8 ommon Side Effects and Supportive Care During Radiation C Therapy Common Acute Side Effects Uncommon Early Side Effects Supportive Care During Treatment Follow-Up After Treatment 193 193 193 193 194 9.8.1 9.8.2 9.8.3 9.8.4 References 194 Abbreviations EORTC 3DCRT FFTF GELA ABVD AP-PA ASCT ASH BEACOPP BV CR CT CTV CVRT DIBH EBVP EFS Three-dimensional conformal radiotherapy Adriamycin (doxorubicin), bleomycin, vinblastine, dacarbazine Opposed anterior and posterior fields Autologous stem cell transplantation American Society of Hematology Bleomycin, etoposide, doxorubicin, cyclophosphamide, procarbazine, prednisone Brentuximab vedotin Complete response Computed tomography Clinical target volume Consolidation volume radiation therapy Deep-Inspiration Breath Hold Epirubicin, bleomycin, vinblastine, dacarbazine Event-free survival GHSG HL IFRT IMRT INRT ISHL11 ISRT LPHL MOP-BAP MOPP MSKCC MTD European Organisation for Research and Treatment of Cancer Freedom from treatment failure Groupe d’Études des Lymphomes Adultes German Hodgkin Study Group Hodgkin lymphoma Involved-field radiation therapy Intensity-modulated radiation therapy Involved-node radiation therapy International Symposium on Hodgkin Lymphoma 2018 meeting Involved-site radiation therapy Lymphocyte-predominant HL Mechlorethamine, vincristine, prednisone, bleomycin, doxorubicin, procarbazine Mustargen, vincristine, procarbazine, prednisone Memorial Sloan Kettering Cancer Center Maximum tumor dimension 9 Principles of Radiation Therapy for Hodgkin Lymphoma NCCN OS PET PTV RT STLI TLI TSH 9.1 National Comprehensive Cancer Network Overall survival Positron emission tomography Planning target volume Radiation therapy Subtotal lymphoid irradiation Total lymphoid irradiation Thyroid-stimulating hormone Principles of Radiation Therapy of Hodgkin Lymphoma 173 stages of HL. In early-stage HL, multiple randomized studies have shown that the omission of RT results in inferior progression-free survival even after chemo-intensification. 3. Modern RT for HL treats only involved sites to reduced doses and is both better tolerated and associated with significantly lower risk for long-term morbidities than the large-field, high-dose RT used as a single modality in the past [3]. 9.2 The Evolution of Radiotherapy for HL RT has been used in the management of HL since Radiation therapy (RT) is a major component of shortly after the discovery of X-rays [4, 5]. the successful treatment of Hodgkin lymphoma Initially, it was used for local palliation, but care(HL). For decades, RT was used alone to cure the ful study by pioneers in the field including Rene majority of patients with HL, and it is still the Gilbert and Vera Peters demonstrated that more most effective single agent in the oncologic arma- aggressive treatment with higher doses and larger mentarium for this disease [1]. RT alone remains fields resulted in the cure of many patients, espethe treatment of choice for patients with early- cially those who presented with limited disease stage lymphocyte-predominant HL (LPHL) and [6, 7]. At Stanford, Henry Kaplan, advantaged by for selected patients with classic HL who have access to the medical linear accelerator, refined contraindications to chemotherapy [2].Currently, the RT concepts and together with Saul Rosenberg most patients with HL are treated with combined- advocated strongly for the curative potential of modality programs in which RT is given as con- RT [8]. RT as a single modality remained the solidation after chemotherapy. As the role of RT standard therapy for patients until effective chehas transformed over the years from a single motherapy was developed in the second half of modality into a component of combined-modality the twentieth century. The success of chemothertherapy, the classic principles of RT fields, dose, apy along with the awareness of adverse late and technique have fundamentally changed. events linked to RT initially led to a decrease in The following principles guide the current its use, but the eventual realization that its judistrategy of using RT in HL: cious application in lower doses and to more tailored fields could enhance curability and allow a 1. RT as part of a combined-modality program is meaningful decrease in chemotherapy doses led radically different from the large-field, high- to the development of combined-modality dose RT that was used as a single modality in programs. the past. Both the volume treated and the dose The RT of modern combined-modality therrequired are significantly reduced following apy programs includes the use of very limited chemotherapy as compared to when RT was treatment volumes and the employment of used alone. In addition, the planning and deliv- advanced techniques that improve conformity ery of RT has improved substantially over the and dose homogeneity. In contrast to RT fields of last two decades and continues to improve. the past, which were based upon bony landmarks, 2. Adding RT to chemotherapy improves disease these field reductions require detailed clinical control and allows the administration of shorter information to delineate the target accurately. and less toxic chemotherapy regimens for all Both pre- and post-chemotherapy imaging are J. Yahalom et al. 174 essential to define the tumor volume and the integration of computed tomography (CT), and positron emission tomography (PET)/CT treatment planning further improves accurate RT volume design. A margin of safety to address subclinical disease and random and systematic positioning error is still necessary in treatment setup, but techniques to minimize inaccuracies in treatment planning and delivery continue to develop. The current recommended RT volume is involved-site radiation therapy (ISRT), which uses pre- and post-chemotherapy CT imaging to tailor the radiation volumes to include only the initially involved lymph node sites and residual CT abnormalities. ISRT represents a significant reduction from the previous customary involved-field RT, which was based on bony landmarks visualized on 2D imaging. Involved-node radiation therapy (INRT) is an even more restricted form of ISRT and is recommended only when detailed pre-chemotherapy imaging in the treatment position is available [9]. The volumes for ISRT and INRT were designed to be smaller than the classic IFRT fields that encompassed the entire predefined anatomical regions. Recommendations for ISRT and INRT design have been established, and INRT has already been incorporated in combined-modality clinical trials in the European Organisation for the Research and Treatment of Cancer (EORTC) and the German Hodgkin Study Group (GHSG) [10]. Recommendations for ISRT design have recently been established by the International Lymphoma Radiation Oncology Group (ILROG), and ISRT has been incorporated into pediatric and adult guidelines and clinical trials in North America and Europe [2, 11, 12]. 9.3 Indications for Radiation Therapy in HL It is important to distinguish between classic HL and nodular lymphocyte-predominant HL (LPHL). The management of each entity is different. Most patients with stage I–II LPHL may be treated with radiation alone with curative intent, whereas combined-modality therapy is the standard approach for the majority of patients with classic HL. 9.3.1 Lymphocyte-Predominant HL Over 75% of patients with LPHL present with stage IA or IIA disease. In this setting, the disease is commonly limited to one peripheral site (neck, axilla, or groin), and involvement of the mediastinum is extremely rare. The National Comprehensive Cancer Network (NCCN) guidelines [2], the German Hodgkin Lymphoma Study Group (GHSG), and the European Organisation for Research and Treatment of Cancer (EORTC) currently recommend limited radiation (IFRT or ISRT) as the treatment of choice for early-stage LPHL. Since the mediastinum is rarely involved, it does not need to be prophylactically treated, thus avoiding the site most responsible for radiation- related short- and long-term side effects. In a recent retrospective study of 131 patients with stage IA disease, 98% of patients obtained a complete response (CR), 98% after extended-field RT alone, 100% after involved- field RT alone, and 95% after combined-modality therapy [13]. With a median follow-up of 43 months, only 5% of patients relapsed and only three patients died. Toxicity of treatment was generally mild and was the greatest in association with combined-modality therapy. Two other studies from the Peter MacCallum in Australia and the Dana-Farber Cancer Institute in Boston supported the adequacy of limited-field RT for LPHL and suggested a reduced risk of second tumors compared to extended-field RT [14, 15]. Although there has not been a prospective study comparing extended-field RT, which was commonly used in the past, and IFRT/ISRT, retrospective data suggest that the more limited fields are adequate [15, 16]. The radiation dose recommended is 30–36 Gy, with the higher dose reserved for bulky sites. 9.3.2 Classic Hodgkin: Stage I–II Over the last two decades, the treatment of stage I–II classic HL has changed markedly. Combined- modality therapy consisting of short-course chemotherapy, most often ABVD, followed by reduced-dose IFRT/ISRT carefully directed only to the involved lymph node(s) has replaced RT 9 Principles of Radiation Therapy for Hodgkin Lymphoma alone as the treatment of choice. Combined modality is the standard treatment for favorable and unfavorable presentations of stage I–II disease in Europe, including the EORTC and GHSG. In the United States, chemotherapy followed by ISRT is the preferred treatment recommended by the NCCN guidelines [2]. Several randomized studies have demonstrated that excellent results in stage I–II HL may be obtained with combined-modality treatment that includes only IFRT and that more extensive fields of total or subtotal lymphoid irradiation (STLI and TLI) are not required [17]. The strategy to reduce the number of chemotherapy cycles and/or the radiation dose was tested by two large-scale randomized non- inferiority studies conducted by the GHSG. In the HD10 study, 1370 patients with early favorable HL were randomly assigned in a 2 × 2 factorial design to receive either four or two cycles of ABVD followed by 30 or 20 Gy IFRT. The 8-year freedom from treatment failure (FFTF) and overall survival (OS) for all patients were 87% and 95%, respectively. Most importantly, there were no significant differences between patients receiving the minimal treatment of ABVD x two cycles followed by IFRT of only 20 Gy and patients receiving more chemotherapy and/or more RT [18]. Patients with unfavorable early- stage HL were randomized on the GHSG HD11 to receive either four cycles of ABVD or four cycles of baseline BEACOPP, followed by IFRT of either 30 or 20 Gy. Fiveyear FFTF and OS for all patients were 85% and 94.5%, respectively. There was no difference in FFTF when BEACOPP × 4 cycles was followed by either 30 or 20 Gy, and similar excellent results were obtained with ABVD × 4 cycles and IFRT of 30 Gy. Patients who received ABVD×4 cycles and only 20 Gy had a FFTF that was lower by 4.7%, but OS was similar in all treatment groups [19]. Finally, the EORTC H9U study investigated three different chemo regimens all followed by consolidative 30–40 Gy IFRT. The results showed that ABVD × 4 cycles and BEACOPP × 4 cycles were not inferior to ABVD × 6 cycles with 5-year EFS of 86%, 89%, and 90%, thus leading to the conclusion that ABVD × 4 cycles followed by IFRT yields high 175 disease control in early unfavorable HL [20]. These large trials of the GHSG and the EORTC have established combined- modality therapy with reduced-field RT as the treatment of choice for patients with stage I–II disease. Recently, trials utilizing results of interim PET scans that were performed after two or three cycles of ABVD to identify possible patients who may be treated with chemotherapy alone have been reported [21–23]. In the UK RAPID trial, researchers tested a chemotherapy-alone treatment program for patients with favorable stage I–II HL who had a negative PET, defined strictly as Deauville 1–2 only, after three cycles of ABVD. They found that ABVD × 3 cycles was inferior to combined-modality therapy in a per- protocol analysis in which randomized groups were analyzed as treated; progression-free survival was significantly better for patients who received consolidative RT (HR 2.36 in favor of IFRT, p = 0.02) [23]. Most recently, in data presented at the International Symposium on Hodgkin Lymphoma 2018 meeting (ISHL11) in Cologne, Germany, additional analysis of the UK RAPID study found that as maximum tumor diameter (MTD) increased, so did the risk of relapse, specifically in patients who did not receive RT. For patients with an MTD < 5 cm, 5-year event-free survival was 93.6% where as it was 79.3% in patients with an MTD ≥ 5 cm (HR 1.23 [95% CI: 1.01–1.48], p = 0.04) [24]. Similarly, a chemotherapy-alone approach has been proven inferior by the EORTC H10 trials for patients with favorable and unfavorable stage I–II HL. In the EORTC H10F and H10U trials, the ABVD-alone arms for patients who were PETnegative (Deauville <3) after ABVD × 2 cycles were terminated early due to an excess number of events when radiation therapy was not incorporated into the therapy even though RT omission was compensated for by an intensification in the number of cycles of ABVD [22]. In the final analysis of the favorable subset of H10, ABVD with INRT resulted in a 5-year PFS of 99.0%, while ABVD alone resulted in a 5-year PFS of only 87.1%. Similarly, in the unfavorable subset, noninferiority also could not be demonstrated with chemotherapy alone as the 5-year PFS was 92.1% in the combined-modality arm and 89.6% in the J. Yahalom et al. 176 chemotherapy-alone arm. Thus, H10 concluded that combined modality with ABVD and INRT remained the standard of care for patients with either favorable or unfavorable stage I–II HL [25]. Most recently, the GHSG presented the results of HD16 at the ISHL11 and the American Society of Hematology (ASH) 2018 meetings. Patients with early-stage favorable HL were randomized to either a standard arm of ABVD × 2 cycles followed by 20 Gy IFRT versus an experimental arm of no further therapy if they were PET- negative, defined as Deauville 1–2, at the end of two cycles of ABVD. The initial analysis, which included Deauville 1–3 patients, showed the omission of RT resulted in inferior outcomes for these favorable-risk patients with a 5-year estimated PFS of 93.4% in the combined-modality arm and 86.1% in the chemotherapy-alone arm. The difference of −7.3% [95% CI: −13.0%, −1.6%] could not exclude the prespecified non- inferiority margin of 3.01%, and thus, combined modality with ABVD × 2 cycles followed by 20 Gy of radiation remains the standard of care for patients with early-stage favorable HL [26]. Finally, the UK RATHL trial, though advertised as a trial for advanced-stage HL, actually was comprised of approximately 50% of patients with stage II disease [27]. This included patients with B symptoms, large mediastinal adenopathy, or >2 sites of disease. Patients with a negative interim PET (Deauville <4) were treated with ABVD or ABVD/AVD chemotherapy alone, without RT. The 3-year PFS was a respectable 90.0%, and the authors conclude that this is acceptable. However, patients on the H10U trial who were treated with just four cycles of ABVD followed by consolidative RT had a 3-year PFS of 95% (Table 9.1). Thus, we have learned from GHSG HD8 that reducing the irradiated volume from the extended- field RT that was used in the era before adequate systemic therapy to involved-field RT does not result in inferior outcomes. We have also learned from GHSG HD10 and HD11 that combined modality with reduced dose and reduced-volume RT after systemic therapy results in excellent outcomes for patients with early-stage HL. Finally, we may conclude from the UK RAPID, EORTC H10, and GHSG HD11 trials that the omission of RT results in inferior outcomes and combined modality remains the standard of care. This conclusion has been further bolstered by a recent systematic review, in which combined-modality treatment was found to improve tumor control and overall survival in patients with early-stage Table 9.1 Summary of trials for stage I–II Hodgkin lymphoma in the PET era (Courtesy of Dr. Richard Hoppe, Stanford University, United States of America) Study NCIC CTG HD.6 [28] Definition of PET negative CT CR/cru RAPID [23] (per protocol) EORTC/GELA/FIL H10F [25] EORTC/GELA/FIL H10U [25] GHSG HD16 [26] D<3 Israeli [29] D<4 CALGB/Alliance 50604 [30] RATHL [27] D<4 Total chemo CR/cru ABVD × 4 PR ABVD × 6 (5) ABVD × 3 ABVD × 3 + RT ABVD × 4 ABVD × 3 + RT ABVD × 6 ABVD × 4 + RT ABVD × 2 + RT ABVD × 2 ABVD × 2–4 + RT ABVD × 4–6 ABVD × 4 D<4 A(B)VD × 6 D<3 D<3 D<3 PFS (%) (years) 95 (5) 81.0 (5) 97.1 (3) 90.8 (3) 87.1 (5) 99.0 (5) 89.6 (5) 92.1 (5) 93.4 (5) 86.1 (5) 98.5 (5) 88.6 (5) 92.0 (3) 90.0 (3) PFS diff OS 94 (12) 6.3 97.1 (3) 11.9 100 (5) 99.6 (5) 98.3 (5) 96.7 (5) 98.1 (5) 98.4 (5) 2.5 7.3 Notes Excludes B sx, bulk Excludes B sx, bulk EORTC favorable EORTC unfavorable GHSG favorable 9.9 Non- randomized B sx, bulk, > sites 9 Principles of Radiation Therapy for Hodgkin Lymphoma Hodgkin lymphoma [31, 32]. We acknowledge there may be select early-stage HL patients for whom a chemotherapy-alone approach may be preferred. A commonly cited example is a young woman who would likely receive a large volume of radiation to breast tissue due to her anatomy or localization of disease in the mediastinum and axillae. It is our recommendation that these patients are discussed in a multidisciplinary conference prior to the start of treatment and that patients are made aware of all possible treatment options so that their preferences may be considered. 9.3.3 Stage III–IV HL Although the role of consolidative RT after induction chemotherapy in stages III–IV remains controversial, RT is often added in patients who present with bulky disease or who do not have a clear complete remission after chemotherapy [33]. The results of prospective studies testing the concept have been conflicting. A meta-analysis of several randomized studies demonstrated that the addition of radiotherapy to chemotherapy reduces the rate of relapse but did not show survival benefit for combined modality compared to chemotherapy alone [34]. Unfortunately, nearly all studies that addressed the question of adding RT in stage III–IV disease were conducted in the pre-PET era. With interim PET imaging, it is possible that a more selective use of RT would prove its benefit. For historical context, we will briefly discuss three main pre-PET era studies. The EORTC 20884 trial was a randomized study that evaluated the role of IFRT in patients with stage III–IV Hodgkin disease who obtained a CR after MOPP/ ABV chemotherapy [35]. Patients received six or eight cycles of MOPP/ABV (number of cycles depended upon the response). Patients who did not achieve a CR (40%) based upon CT imaging only were not randomized but were all assigned to receive IFRT. Among the 333 randomized patients, the 5-year overall survival rates were 91% (no RT). Among the partial responders after six cycles of MOPP/ABV, the addition of IFRT 177 yielded overall survival and event-free survival rates that were similar to those obtained among patients who achieved a CR to chemotherapy. This suggests a key role for consolidative RT in stages III–IV when patients fail to achieve a complete response to chemotherapy. Unfortunately, MOPP/ABV is toxic and has been abandoned for use in North America. A more modern randomized study evaluated the role of consolidation RT after CR to chemotherapy used ABVD × 6 cycles, which is the most common regimen currently used for advanced-stage HL. This trial was conducted at the Tata Medical Center in India. It included patients of all stages, but nearly half were stages III–IV. A subgroup analysis of these patients showed a statistically significant improvement of both 8-year event-free survival (EFS) and 8-year overall survival with added RT compared to ABVD alone (EFS 78 vs. 59%; p < 0.03 and OS 100 vs. 80%; p < 0.006) [36]. Finally, a secondary analysis of the UKLG LY09 study evaluated the effect of consolidation RT following different chemotherapy regimens in advanced-stage patients. Although more patients with bulky disease and partial response were in the RT group, PFS and overall survival were significantly better for 43% of the patients who received RT in this study. Subgroup and multivariate analysis confirmed this benefit from additional RT [37]. The first study to incorporate PET imaging in an attempt to define the more selective use of RT was the GHSG HD15 trial. In this trial, patients with advanced disease were treated with different schedules of BEACOPP chemotherapy. Following completion of chemotherapy, patients with residual disease greater than 2.5 cm underwent PET imaging. If the PET scan was negative, patients received no further therapy. If the PET scan was positive, the patients received 30 Gy of consolidative RT. Although the group with a positive PET scan had a worse PFS than the PET- negative group (86.2% vs. 92.6%), the results in the PET-positive group were actually quite good for this subset of poor-prognosis patients, supporting the use of RT for patients in PR by PET following completion of chemotherapy [38]. Another recent trial evaluated the role of RT J. Yahalom et al. 178 among stage IIB–IVB patients who had interim and end-of-treatment PET-negative disease [39]. The GITIL/FIL HD 0607 trial randomized patients who had nodal disease >5 cm to receive no further treatment or consolidative RT to the initially bulky sites following ABVD × 6 cycles. With a median follow-up of 3.6 years, there was no significant difference in PFS (93% vs. 97% at 3 years, p < 0.3) or OS (99% vs. 100%, p < 0.08). The RT question was not addressed for patients who failed to achieve a complete metabolic response following the completion of chemotherapy. Finally, the US Intergroup trial S0816 treated patients with chemotherapy alone, including chemotherapy escalation for patients who had an interim-positive PET [40]. Among patients who had an end-of-treatment positive PET, the 2-year PFS was only 30.6%. Although no RT was utilized for these patients, an analysis was completed assuming patients who met the GHSG HD15 criteria were irradiated [41]. Assuming a modest 50% local control for RT, this would have boosted the likely PFS from 30.6% to 42.8%. Assuming a more likely 80% local control for RT, this would have boosted the 2-year PFS to 50.2%. In summary, the data from the EORTC 20884 and GITIL/FIL HD 0607 suggest a limited role for RT among patients who achieve a complete response to chemotherapy. In contrast, the EORTC 20884, GHSG HD15, and special analysis of the US Intergroup S0816 trial all suggest that patients who fail to achieve a CR to chemotherapy are very likely to be benefited by the incorporation of RT. Some patients may benefit simply from consolidative RT at the conclusion of chemotherapy, while others may benefit from its inclusion in an overall salvage treatment program. 9.3.4 T in Salvage Programs R for Refractory and Relapsed HL High-dose therapy supported by autologous stem cell transplantation (ASCT) has become a standard salvage treatment for patients with HL who relapse or remain refractory to primary therapy. Many of these patients have not received prior RT or have relapsed at sites outside the original radiation field. These patients could benefit from integrating RT into the salvage regimen. Poen and colleagues from Stanford analyzed the efficacy and toxicity of adding cytoreductive or consolidative RT to 24 of 100 patients receiving high-dose therapy [42]. When involved sites were irradiated in conjunction with transplantation, no in-field failures occurred. While only a trend in favor of IFRT could be shown for the entire group of transplanted patients, analysis restricted to patients who had no prior RT or those with relapse stages I–III demonstrated significant improvement in freedom from relapse. Fatal toxicity in this series was not influenced significantly by IFRT. Similar improvements in outcomes by the addition of RT have been demonstrated in multiple other series including studies from the University of Rochester [43] and the University of Torino [44]. At MSKCC, a program that integrated RT into the high-dose regimen for salvage therapy was developed and included accelerated hyperfractionated irradiation (twice daily fractions of 1.8 Gy each) to start after the completion of reinduction chemotherapy and stem cell collection and prior to the highdose chemotherapy and stem cell transplantation [45–47]. Patients who had not been previously irradiated received involved-field RT (18 Gy in 5 days) to sites of initially bulky (>5 cm) disease and/or residual clinical abnormalities, followed by total lymphoid irradiation (TLI) of 18 Gy (1.8 Gy per fraction, bid.) during an additional 5 days. Patients who had prior RT received only involved-field RT (when feasible) to a maximal dose of 36 Gy. A recent report detailed the outcomes of 186 patients treated from 1985 to 2008. The 10-year OS and EFS were 56% [48]. The authors concluded that this was a safe and effective salvage strategy. A report on the quality of life and treatment-related complications of this program disclosed only a small number of late complications [49]. ILROG has published consensus guidelines regarding best practice for inclusion of RT in salvage treatment programs for Hodgkin lymphoma [50]. This report details the patient variables that 9 Principles of Radiation Therapy for Hodgkin Lymphoma affect selection of salvage treatment, including intensity of prior therapy, extent of relapse, whether disease is chemorefractory, and how radiation can best be incorporated into effective salvage therapy. 9.4 Mantle Radiation Fields and Volumes: Principles and Design In the past, radiation-field design attempted to include multiple involved and uninvolved lymph node sites. The large fields known as mantle, inverted Y, and TLI were synonymous with the radiation treatment of HL. These fields are no longer in use. IFRT encompasses a significantly smaller volume and was incorporated into many clinical trials of the past two decades. Extending this concept further, even more limited radiation volumes termed involved-node radiation therapy (INRT) and involved-site radiation therapy (ISRT) have been introduced into combined- modality programs and endorsed by guideline groups as the new standard RT volumes for HL [9, 10]. Even when radiation is used as primary management for LPHL, the treatment volumes should be limited to the involved site or to the involved sites and immediately adjacent the lymph nodes. The terminologies that define radiation volumes may be confusing and create difficulties in comparing treatment programs. However, general definitions and guidelines are now available and should be followed [9]. The following are definitions of types of radiation fields and volumes that have been used in HL. 9.4.1 179 Extended-Field Radiation Therapy This field includes the involved lymph node group plus the adjacent clinically uninvolved region(s). For extranodal disease, it includes the involved organ plus the clinically uninvolved lymph node region. It was common during the Paraaortic Pelvic Fig. 9.1 Illustration of extended RT fields used in the past era of treatment with RT alone to treat large fields encompassing multiple lymph node regions, both involved and uninvolved. The field design that includes all of the supradiaphragmatic lymph node regions was referred to as the mantle field. The field that includes all lymph node sites below the diaphragm (with or without the spleen and called after its shape) is the inverted Y. When all the major lymph node regions above and below the diaphragm were irradiated, this was referred to as total lymphoid irradiation (Fig. 9.1). If the pelvic nodes were not included, this was referred to as subtotal nodal irradiation. Extended fields are rarely used in modern treatment of HL. 9.4.2 Involved-Field Radiation Therapy These fields are limited to the clinically involved lymph node regions [51]. It was influenced by lymphoid regions that were defined in the Ann Arbor staging system for Hodgkin’s disease [52]. For extranodal sites, the field includes the organ alone (if no evidence for lymph node J. Yahalom et al. 180 involvement). IFRT was commonly employed in clinical trials during the past two decades, but fields have now become even smaller as 3D cross-sectional imaging has become widely available. The new volumes based on CT-based simulation are involved-node radiation therapy (INRT) and involved-site radiation therapy (ISRT). 9.4.3 Involved-Site Radiation Therapy (ISRT): The New Standard Volume for HL The International Lymphoma Radiation Oncology Group (ILROG) now recommends the use of ISRT to treat HL [9]. ISRT has already been adopted as the standard volume by several organizations including the NCCN [2]. In the majority of cases, assuming the same clinical presentation and response, ISRT is smaller than IFRT and more precise as treatment volumes are determined by modern cross-sectional imaging such as CT and PET-CT rather than by standard bony landmarks of the involved location as seen on 2D imaging. The concept of ISRT was developed as an extension of the INRT concept that was conceived earlier [10]. In comparison to INRT, ISRT allows for more flexibility and use of clinical judgment when the strict criteria for INRT pre-chemotherapy imaging cannot be met. Indeed, in the majority of practices, preresection or pre-chemotherapy precise imaging is not available in the radiation treatment position. ISRT accounts for this deficiency. INRT is fundamentally a more optimal case of ISRT when accurate pre-chemotherapy imaging allows for tighter margins around the original volumes. Finally, unlike IFRT, which uses predetermined anatomical regional “borders” determined by bony landmarks that are easy to visualize during conventional 2D simulation, which has now been replaced by CT or PET/ CT simulation, ISRT and INRT incorporate the current concepts of volume determination as outlined in the ICRU Report 83 [53]. The modern RT treatment volumes are based on defining a gross tumor volume (GTV), a clinical target volume (CTV), and a planning target volume (PTV). The PTV is then used to define beam coverage. 9.4.3.1 I SRT When RT Is the Primary Treatment RT as single modality in HL is relevant for stage I–II lymphocyte-predominant Hodgkin lymphoma (LPHL). It may also be relevant in selected cases of early-stage classic HL in patients who are not candidates for primary chemotherapy due to serious comorbidities. In most clinical situations that require RT as the primary modality, the GTV should be readily visualized during simulation. In this situation, the clinical target volume (CTV) should be more generous since microscopic or subclinical disease is more likely to be present without chemotherapy. 9.4.3.2 I SRT When RT Is Part of Combined-Modality Treatment RT is often part of the treatment program for early-stage classic HL following adequate systemic chemotherapy. RT improves freedom from treatment failure and progression-free survival even in patients with a negative interim PET [22, 23, 26,] and allows for a reduced number of chemotherapy cycles [18]. In a recent systematic review, combined-modality treatment was found to improve tumor control and overall survival in patients with early-stage Hodgkin lymphoma [29]. In select patients with advanced-stage disease, localized RT may be used for residual sites of lymphoma after full course of chemotherapy [39]. The GTV may be markedly affected by prior systemic chemotherapy, and it is therefore particularly important to review the pre-chemotherapy imaging and to define the pre- chemotherapy volume on the 9 Principles of Radiation Therapy for Hodgkin Lymphoma simulation CT study as “pre-chemotherapy GTV” as well as the post-chemotherapy remaining CT and/or PET abnormality as “post-chemotherapy” GTV. 181 INRT was originally developed and implemented by the EORTC to replace IFRT in prospective randomized studies (EORTC/GELA/ IIL H10). It mandated accurate PET/CT information prior to chemotherapy and in a position similar the subsequent post-chemotherapy radiation therapy treatment position. The INRT technique reduces the treated volume to a minimum, but in order to be safe, optimal imaging both before and after chemotherapy is needed [9, 38]. INRT represents a special case of ISRT, where pre-chemotherapy imaging is ideal for post-chemotherapy treatment planning (Fig. 9.2). PET/CT up front for staging purposes is mandatory as it has been demonstrated that PET/CT is the most accurate imaging method for determining disease extent in HL [39]. In order to enable image fusion of the pre-chemotherapy and the post-chemotherapy planning images, the pre-chemotherapy PET/ CT scan should be acquired with the patient in the treatment position and using the same breathing instructions that will be used later for RT. Ideally, the patient should be scanned on a flat couch top, with the use of appropriate immobilization devices and using markers at skin positions which are visible in the imaging. During or following the completion of chemotherapy, a response assessment using PET/CT or contrast-enhanced CT should be performed. A planning CT scan is acquired with the patient in the same position as in the pre-chemotherapy CT scan. This highly conformal treatment technique has been shown to be safe, provided strict adherence to the principles above is maintained [54–56]. Fig. 9.2 Involved-node radiation therapy. Single lymph node in the left lower neck prior to chemotherapy (left) and following chemotherapy (right). The border of the field encompasses the original volume of the node and not of the whole unilateral neck (as in IFRT approach) (Courtesy of Dr. Theodore Girinsky, Institute Goustave-Roussy, France) 9.4.4 Involved-Node Radiation Therapy (INRT): A Special Case of ISRT J. Yahalom et al. 182 9.4.5 Volume Definitions for Planning ISRT and INRT These principles apply regardless if RT is used as primary treatment or as part of combined modality and are relevant to both involved-site radiation therapy (ISRT) and involved-node radiation therapy (INRT). The only difference between ISRT and INRT is the quality and accuracy of the pre-chemotherapy imaging, which determines the margins needed to allow for uncertainties in the contouring of the clinical target volume (CTV). 9.4.5.1 Volume of Interest Acquisition Planning RT for lymphoma is based on obtaining a three-dimensional (3D) simulation study using either a CT simulator, a PET/CT simulator, or an MRI simulator. If PET and/or CT information has been obtained separately or prior to simulation, it is possible to transfer the data either manually or electronically into the simulation CT data. Ideally, any imaging studies that provide planning information should be obtained in the treatment position and using the planned immobilization devices. 9.4.5.2 Determination of Gross Tumor Volume (GTV) Pre-chemotherapy (or Presurgery) GTV Any abnormalities on imaging studies obtained prior to any intervention that might have affected lymphoma volume should be outlined on the simulation study, as these volumes should (in most situations) be included in the CTV. No Chemotherapy or Post-chemotherapy GTV The primary imaging of untreated lesions or post-chemotherapy residual GTV should be outlined on the simulation study and is always part of the CTV. 9.4.5.3 Determination of Clinical Target Volume (CTV) CTV encompasses in principle the original (prior to any intervention) GTV. Yet, normal structures such as the large vessels, lungs, kidneys, and muscles that were clearly uninvolved should be excluded from the CTV based on clinical judgment. In outlining the CTV, the following points should be considered: (a) Quality and accuracy of imaging and transfer of volumes to simulation images. (b) Concerns of changes in volume since imaging. (c) Patterns of spread. (d) Potential subclinical involvement. (e) Adjacent organs constraints. If separate nodal volumes are involved, they can potentially be encompassed in the same CTV. However, if the involved nodes are >5 cm apart, they can be treated with separate volumes using the CTV-to-PTV expansion guidelines as outlined further. 9.4.5.4 Determination of Internal Target Volume (ITV) ITV is defined in the ICRU Report 62 [54] as the CTV plus a margin that accounts for uncertainties in size, shape, and position of the CTV within the patient. The ITV is mostly relevant when the target is moving with respiration, most commonly in the chest and upper abdomen. The optimal way to manage respiratory motion is to use 4D-CT simulation to understand target movement and to generate accurate ITV margins or to use breath-hold techniques. Alternatively, the ITV may be determined by fluoroscopy or estimated by an experienced clinician. In the chest or upper abdomen, margins of 1.5–2 cm in the superior- inferior direction may be necessary. In sites such as the neck, which are well immobilized and unlikely to change shape or position during or in between treatments, outlining the ITV is not required. 9.4.5.5 Determination of Planning Target Volume (PTV) PTV is the volume that considers the CTV (or ITV, when relevant) and also accounts for setup uncertainties in patient positioning and alignment of the beams during treatment planning and through all treatment sessions. The practice of determining the PTV varies across institutions. 9 Principles of Radiation Therapy for Hodgkin Lymphoma The clinician and/or treatment planner adds the PTV and applies standard margins that depend on estimated setup variations that are a function of immobilization device, body site, and patient cooperation. While standard patient setup has historically been done based on skin marks and weekly portal films, daily image-guided RT (IGRT) has allowed for reduction in PTV margins. The smaller margins are a function of more certainty with setup, which can ultimately help reduce the radiation dose to the normal structures. IGRT can include daily orthogonal KV images or cone beam CT scan (KV or MV). In general, PTV expansions can range from 0.3 to 1.0 cm depending on the location and use of IGRT. 9.4.6 Determination of Organs at Risk (OAR) The OARs are normal structures that, if irradiated, could result in significant morbidity including acute toxicity, such as pneumonitis and esophagitis, and late toxicity, such as hypothyroidism, cardiac toxicity, and second cancers. OARs may influence treatment planning or the prescribed dose. They should be outlined on the simulation study. Dose-volume histograms (DVH) and normal tissue complication probability (NTCP) should be calculated by the planner and the plan vetted by the clinician in consideration of this information. Of note, the general principle with regard to OARs in HL should always be ALARA—as low as reasonably achievable—and should depend on the disease distribution, planned treatment volume, and total dose. 9.4.6.1 Lung A major concern for patients with HL and mediastinal disease who receive RT is pneumonitis with grade 3 pneumonitis rates as high as 7% reported by the MD Anderson Cancer Center (MDACC) following IMRT. This is especially true if given as part of second-line therapy and transplant. The MDACC group evaluated factors predictive of grade 1–3 pneumonitis (14% overall) and found 183 the risk of radiation pneumonitis increases with mean lung dose >13.5 Gy, V20 > 30%, V15 > 35%, V10 > 40%, and V5 > 55%. Of note, the strongest predictor was V5 with V5 > 55% associated with a risk of pneumonitis of almost 35% [57]. 9.4.6.2 Heart Multiple studies have explored the relationship of heart dose and cardiac toxicity and death among HL survivors. Cardiac toxicity may be due to pericarditis, arrhythmia, coronary artery disease, valvular disease, and cardiomyopathy/congestive heart failure. Dosimetric factors have been identified that have been associated with increased risk of cardiac toxicity. Van Nimwegen et al. reported on a cohort of HL survivors from the Netherlands and found a mean heart dose correlated well with coronary heart disease, demonstrating an excess relative risk of 7.4% per Gy mean heart dose [58]. A statistically significant increased risk of coronary heart disease was demonstrated among patients getting a mean heart dose as low as 5–14 Gy (RR 2.31) compared with a mean heart dose of 0 Gy. This risk was even higher for mean heart dose of 15 Gy or higher (RR 2.83 for 15–19 Gy, 2.9 for 20–24 Gy, and 3.35 for 25–34 Gy). A recent analysis of 24,214 5-year survivors of childhood cancer in the Childhood Cancer Survivor Study provided substantial insights into the relationships between radiation and risk of long-term cardiac disease. Mean heart doses >10 Gy were associated with increasing cardiac disease risk in a dose-response manner. Volumes of the heart receiving radiation also were correlated with cardiac risk; children receiving a V5 of >50% had a 1.6-fold increased risk of late cardiac disease. Those receiving at least 20 Gy to any part of the heart also were at increased risk. Current recommendations are to keep the mean heart dose as low as possible with stricter goals to try and keep the mean heart dose <15 Gy in adults and <10 Gy in pediatrics whenever possible. Rarely, should mean heart doses greater than 20 Gy be used, unless patients are being treated definitively in the salvage setting [59]. While mean heart dose may be appropriate for radiation evaluation for IFRT, it is unclear whether it is as important when more conformal techniques J. Yahalom et al. 184 are being used, which can redistribute the dose [60]. Recent studies have demonstrated radiation dose relationships with specific cardiac substructures. For example, Van Niwmegen demonstrated a relationship between heart failure and mean dose to the left ventricle [56]. Among patients treated with anthracyclines, the 25-year cumulative risk of heart failure was 11.2% for mean LV dose <15 Gy, 15.9% for 16–20 Gy, and 32.9% for greater than or equal to 21 Gy. Another study by Cutter et al. demonstrated 30-year cumulative risks of valvular heart disease of 3%, 6.4%, 9.3%, and 12.4% for mean valvular dose of <30, 31–35, 36–40, and >40 Gy [61]. Based on this data, we would recommend keeping the mean valve dose <30 Gy, mean left ventricle dose <15 Gy, and ideally <5 Gy. 9.4.6.3 Thyroid While hypothyroidism is a common late toxicity, it can be easily managed with thyroid supplementation medication. Cella et al. demonstrated a dose volume effect with 11.5% of patients with hypothyroidism with a V30 < 63% vs. 71% for patients with V30 greater than or equal to 63% [62]. 9.4.6.4 Second Cancers The primary cause of death among long-term survivors of HL is second cancers. The most common among survivors are breast cancer, thyroid cancer, sarcomas (bone and soft tissue), and lung cancer. Risk modeling has identified linear dose risks for all these cancers, except for thyroid cancer. Breast cancer is the most concerning second cancer among female survivors receiving radiation. While smaller treatment fields have greatly reduced the risk of second breast cancers, consideration of breast dose is important in minimizing the risk for all patients. Travis et al. demonstrated that radiation doses >4 Gy were associated with increased risk of secondary breast cancer with increasing dose further increasing the risk. In fact, the relative risk was 1.8 and 4.1 for breast dose of 4–6.9 and 7–23.1 Gy, respectively [63]. Therefore, it is important to keep the mean breast dose as low as possible and try to minimize the breast V4 to as low as possible. Lung cancer is an aggressive second cancer that will often result in death for a HL survivor. Fortunately, the risk can greatly be mitigated for nonsmokers. However, among smokers, this risk is increased significantly with the addition of lung irradiation. Travis et al. demonstrated among HL survivors that lung dose of >5 Gy had a relative risk of 5.9 compared with lung dose <5 Gy for developing a second lung cancer [64]. Similar to concerns of pneumonitis, lung V5 should be evaluated with attempts to keep as low as possible. Secondary sarcomas have also been found to increase with higher radiation doses to the body. Tukenova et al. demonstrated increased risk (12.5) for dying from a secondary sarcoma when the calculated integral dose was >150 J [65]. Thyroid cancers do not have a linear dose-risk relationship with radiation. Bhatti et al. demonstrated a relative risk increase in secondary thyroid cancers of 8.5 with doses of 5–10 Gy, 10.6 for 10–15 Gy, 13.8 with 15–20 Gy, and 14.6 for 20–25 Gy, with relative risks then declining with doses >25 Gy [66]. 9.4.7 Consolidation Volume Radiation Therapy (CVRT) As systemic therapies continue to improve, further reductions in RT volumes may be possible. Currently, there are ongoing studies looking at modifications in systemic therapy to include brentuximab vedotin (BV) and/or checkpoint inhibitors, such as pembrolizumab and nivolumab [67, 68]. One recent reported study from Memorial Sloan Kettering Cancer Center (MSKCC) demonstrated a favorable response to BV-AVD × 4 cycles followed by ISRT [69]. Consolidation volume radiation therapy (CVRT), which treats only residual CT abnormalities in patients who achieve a CR by PET, is currently being tested after BV-AVD × 4 cycles [70]. 9.5 Dose Considerations and Recommendations Although doses in the range of 40–44 Gy were at one time recommended for the definitive treatment of HL, these recommendations have been modified over time, both in the context of 9 Principles of Radiation Therapy for Hodgkin Lymphoma combined- modality therapy for cHL and the treatment of patients with LPHL. The radiation dose is typically delivered in 1.8–2.0 Gy fractions. If significant portions of lung or heart are included, the dose per fraction can be reduced to 1.5 Gy. The available data indicate that the choice of fractionation is not critical for tumor control and that a schedule with minimal risk of damage to normal structures should be selected. The GHSG evaluated dose in patients with stage IA–IIB disease without risk factors in a randomized trial of 40 Gy extended-field radiation alone vs. 30 Gy extended-field radiation with a boost of 10 Gy to the involved site of disease [71, 72]. There was no significant difference in outcome between the two arms of the study indicating that 30 Gy is sufficient for clinically uninvolved areas when RT is used alone. The optimum dose for clinically involved sites of disease with RT alone has not been tested in a randomized trial. More relevant to current practice is the determination of the adequate radiation dose after treatment with chemotherapy. In many early studies, radiation doses were kept at approximately 40 Gy even after achieving a CR to chemotherapy; others reduced the dose in advanced disease when combined with five cycles of chemotherapy to 20–24 Gy with excellent overall results [73]. Studies of combined modality in advanced stage also used reduced doses of RT for patients who achieved a CR to chemotherapy and higher doses (approximately 30 Gy) for patients in PR. The pediatric groups addressing the concern of radiation effects on skeletal and muscular development also effectively reduced the dose of RT after combination chemotherapy to 21–24 Gy [74]. However, recent reports have demonstrated that >90% of all relapses occur in field, suggesting higher doses may be appropriate for pediatrics in certain cases [75]. Several recent studies addressed the adequacy of low-dose IFRT following chemotherapy. A study conducted by the EORTC/GELA [76] randomized patients with favorable early-stage HL to 36, 20, or no IFRT after achieving a CR to six cycles of EBVP. Because an excessive number of relapses occurred in the no-RT arm, this arm was closed early. There was no difference in EFS at 4 years between patients receiving IFRT 36 Gy (87%) vs. 20 Gy (84%). A GHSG randomized 185 study (HD 10) addressed the radiation dose question after short-course chemotherapy [18]. Patients with favorable stages I–II were randomized to receive either four or only two cycles of ABVD followed by IFRT of 30 or 20 Gy. At a median followup of 7 years, there was no difference in FFTF among the four arms. FFTF at 5 years was 93.4% in patients treated with 30 Gy (91.0–95.2%) and 92.9% in those receiving 20 Gy (90.4–94.8%). These results, taken together with the better tolerability and the lack of inferiority in secondary efficacy endpoints, led to the conclusion that 20 Gy IFRT, when combined with even only two cycles of ABVD, is equally effective to 30 Gy IFRT in this very favorable group of patients [15]. The GHSG HD11 study targeted patients with unfavorable early stage and randomized them to either ABVD × 4 cycles or BEACOPP × 4 cycles; either program was followed by either 20 or 30 Gy to the involved field. Five-year FFTF and OS for all patients were 85% and 94.5%, respectively. There was no difference in FFTF when BEACOP × 4 cycles was followed by either 30 or 20 Gy, and similar excellent results were obtained with ABVD × 4 cycles and IFRT of 30 Gy. Patients who received ABVD × 4 cycles and only 20 Gy had FFTF that was lower by 4%. OS was similar in all treatment groups [19]. These results suggest that 30 Gy should remain the standard IFRT dose following ABVD in unfavorable early-stage HL [77]. For patients with early-stage LPHL, no advantage has been shown for doses over 30–35 Gy [15]. For patients with residual lymphoma after chemotherapy, the residual mass may represent a more refractory disease, and increasing the dose to the CTV to 36–40 Gy should be considered. 9.5.1 he Significance of Reducing T the Radiation Dose Recent studies clearly indicate that the risk of secondary solid tumor induction is radiation dose related. This was carefully analyzed for secondary breast and lung cancers as well as for other tumors [63, 64, 78, 79]. While it will take more years of careful follow-up of patients in randomized studies to display the full magnitude of risk tapering by current reduction of radiation volume and dose, J. Yahalom et al. 186 recent data suggest that this likely to be the case. In a Duke University study, two groups of patients with early-stage HL were treated with different radiation approaches over the same period. One group received RT alone, given to extended fields with a median dose of 38 Gy; the second group received chemotherapy followed by involved-field low-dose (median of 25 Gy) RT. While 12 patients developed second tumors in the first group and 8 of them died, no second tumors were detected in the second group. The median follow-up was 11.7 and 8.1 years, respectively [80]. Similar observations with an even longer follow-up were made by the Yale group [81]. In a study that used data-based radiobiological modeling to predict the radiationinduced second cancer risk, lowering the dose from 35 to 20 Gy and reducing the extended field to IFRT reduced lung cancer risk and breast cancer risk by 57% and 77%, respectively [82]. Finally, a study by a French Collaborative Lymphoma group (GOELAM) randomized patients with favorable stage I–II HL to receive a conservative RT dose of 40 Gy to involved sites and 30 Gy to adjacent site control arm or in the “experimental arm” to receive only 36 Gy and 24 Gy to the adjacent sites after ABVD × 3 cycles [83]. Surprisingly, the 10-year incidence of severe or fatal complications was nil in the experimental arm but reached 15.5% in the control arm (p < 0.003) and 11.1% in the historical controls that received the higher dose. The 10-year FFTF and overall survival rates were similar for the 89 patients in the experimental arm (88.6% and 97.8%, respectively), for the 99 patients in the conservative arm (92.6% and 95%, respectively), and for the 202 patients in the historical control group (91.9% and 92.9%, respectively). 9.5.2 Dose Recommendations Radiation alone (as primary treatment for LPHL) using ISRT • Clinically involved and adjacent uninvolved nodes: 30–36 Gy. Radiation alone (as primary treatment for cHL [uncommon]) • Clinically involved sites: 36 Gy at a minimum. • Clinically uninvolved sites: 30 Gy. Radiation following chemotherapy in a combined-modality program • Patients in CR after chemotherapy: 20–30 Gy. –– For pediatric or adolescent patients: 15–24 Gy. –– In some programs of short chemotherapy for bulky or advanced-stage disease (e.g., Stanford V), the recommended RT dose is 30–36 Gy. • Patients in PR after chemotherapy: 30–40 Gy. 9.6 ew Aspects of Radiation N Volume Definition and Treatment Delivery The abandonment of large-field irradiation for most patients with HL permits the use of more conformal RT volumes and introduction of other innovative RT techniques. The change in the lymphoma RT paradigm coincided with substantial improvement in imaging and treatment planning technology that has revolutionized the field of RT. The integration of fast high-resolution computerized tomography into the simulation and planning systems of radiation oncology has changed how treatment volumes and relationship to normal critical structures are determined and planned. In the recent past, tumor volume determinations were made with fluoroscopybased simulators that produced often poor-quality imaging requiring wide “safety margins” that detracted from accuracy and sparing of critical organs. Most modern simulators are in fact high- resolution CT scanners with software programs that allow accurate conformal treatment planning and provide detailed information on the dose volume delivered to normal structures within the treatment field and the homogeneity of dose delivered to the target. More recently, these simulators have been integrated with a PET scanner that provides additional tumor volume information for consideration during radiation planning. 9 Principles of Radiation Therapy for Hodgkin Lymphoma 9.6.1 New Technologies Intensity-modulated RT (IMRT), tomotherapy, and volumetric modulated arc therapy (VMAT) are advanced systems for photon delivery. These modalities redistribute the radiation to provide high-dose conformality of the target area, but with less conformality in the low-dose region. They also allow for accurately enveloping the tumor with either a homogenous radiation dose (“sculpting”) or delivering higher doses to predetermined areas in the tumor volume (“painting”). In the treatment of lymphoma, there are several clinical situations where highly conformal photon techniques provide a benefit. In the mediastinum, a review article of comparison studies showed that IMRT compared with conventional 3D-conformal radiation techniques reduced the mean heart dose on average by 1.44 Gy, mean esophagus dose by 1.4 Gy, and lung V20 by 11% [84]. Highly conformal photon techniques can also be useful in the treatment of very large or complicated tumor volumes in the abdomen and head and neck lymphomas. IMRT also allows re-irradiation of sites prior to high-dose salvage programs that otherwise will be prohibited by normal tissue tolerance, particularly of the spinal cord (Figs. 9.3a–d and 9.4a–c). In general, when using highly conformal photon techniques for mediastinal disease, treatment planning generally tries to avoid equally spaced beams or continuous arcs around the patient in an effort to avoid some of the low-dose bath, especially to the lungs and breasts. MD Anderson Cancer Center has described both the butterfly IMRT technique and the rainbow IMRT technique as ways to optimize the IMRT beam arrangement in mediastinal lymphoma. In the butterfly technique, three anterior and two posterior beams are used to reduce excess exposure to heart, lungs, and spinal cord. In the rainbow technique, one anterior-posterior (AP) beam and four anterior obliques at 0°, 20–30°, 40–60°, 300–320°, and 335–345° are used for patients with only anterior mediastinal disease [85, 86]. Similarly, the University of Torino evaluated optimized VMAT plans that include non-coplanar partial arcs [87, 88]. Early clinical data has begun to emerge from the use of IMRT for mediastinal lymphoma dem- 187 onstrating similar disease control to 3DCRT treatment [78, 89]. While most have shown little to no pneumonitis with these techniques, MDACC did report a 15% grade 1–3 pneumonitis risk including 6.9% grade 3 rate [58]. 9.6.2 Deep Inspiration Breath Hold An additional technique that can be used to try and further minimize heart and lung dose for mediastinal lymphoma patients and can be used with 3DCRT, IMRT, or proton therapy is deep inspiration breath hold (DIBH). DIBH is a simple technique which the patient inhales deeply and holds this breath during treatment. DIBH can optimize the internal anatomy by pulling the heart caudally while allowing the disease to be irradiated to remain more superiorly by the great vessels for patients with superior mediastinal disease. This allows for more cardiac sparing for these patients. DIBH also immobilizes the disease in the mediastinum, which controls respiratory motion and eliminates the need for an ITV. Finally, it expands the total lung volume, which results in an overall decreased dose to the lungs [90]. Petersen et al. conducted a prospective phase II study of DIBH among patients with mediastinal lymphoma among 19 patients. In the study, the mean lung dose was reduced on average by 2 Gy with DIBH and mean heart dose by 1.4 Gy. Another study by Charpentier et al. reported on 47 patients undergoing DIBH, where the mean lung dose was reduced by approximately 1.5 Gy and mean heart dose reduced by 2.5 Gy [91]. While DIBH appears beneficial for disease located in the superior mediastinum, the benefit is not as obvious for patients with lower mediastinal disease that extends to the level of the heart [92]. This was seen in a study by Paumier et al. who demonstrated a mean heart dose reduction of 50% for patients with upper mediastinal disease, while it was only 8–9% and not significant for lower mediastinum. Similarly, the mean lung dose was reduced by 26% for upper mediastinal disease, but only 18% reduction for lower mediastinal disease [93] (Fig. 9.5). 188 J. Yahalom et al. a b Fig. 9.3 (a) CT-MR fusion for target localization of HL involving the mediastinum and right chest wall. CTV clinical treatment volume, PTV planning treatment volume. (b, c) Treatment plans comparing AP/PA, 3DCRT, and IMRT. PTV planning treatment volume, AP/PA opposed anterior and posterior fields, 3DCRT three-dimensional conformal radiation therapy, IMRT intensity-modulated radiation therapy. (d) Comparison of lung complication probability of different plans 9 Principles of Radiation Therapy for Hodgkin Lymphoma 189 c Plans: d AP/PA 3DCRT IMRT 100 Complication probability (NTCP) for lungs Volume (%) 80 60 AP/PA 3DCRT IMRT 40 20 Lungs 0 0 1,000 2,000 3,000 Dose (cGy) Fig. 9.3 (continued) 4,000 5,000 19% 16% 3% 190 J. Yahalom et al. a b Fig. 9.4 (a) Use of IMRT for re-irradiation of a patient relapsing after ABVD and mantle-field irradiation to 36 Gy. (b, c) Treatment planning options for re-irradiation. AP/PA opposed anterior and posterior fields, 3DCRT three-dimensional conformal radiation therapy, IMRT intensity-modulated radiation therapy 9 Principles of Radiation Therapy for Hodgkin Lymphoma 191 c Fig. 9.4 (continued) Fig. 9.5 An example case in which the use of DIBH increases total lung volume and pulls the heart caudally, thus decreasing dose to lung and heart without compromising coverage (Courtesy of Lena Specht, MD PhD, Rigshospitalet, University of Copenhagen, Denmark) J. Yahalom et al. 192 9.7 Proton Therapy Another technical advance is the use of particle therapy (protons). Protons have the advantage of a more defined depth of penetration than photons, which eliminates the “exit dose” of photons. Proton therapy may be helpful in the mediastinum, in select cases where significant sparing of OARs including the heart, lungs, and esophagus cannot be achieved with IMRT [56]. In a review article of several dosimetric studies comparing highly conformal photon techniques with proton therapy, on average proton therapy reduced the mean heart dose by 2.24 Gy, breast by 2.45 Gy, lung by 3.28 Gy, thyroid by 2.09 Gy, and mean body dose by about 40% [76]. Patients with lower mediastinal disease may benefit more from proton therapy, due to the potential gains in reducing the radiation dose to the heart as described in the ILROG guidelines [94]. The Fig. 9.6 A sample case of an 18-year-old woman with stage II HL at diagnosis with representative plans using various treatment modalities including mantle field, IFRT, ISRT using 3DCRT (ISRT 3D), ISRT using IMRT (ISRT ILROG guidelines also discuss in detail both the advantages and disadvantages of proton therapy for lymphoma and identify parameters that can help clinicians better select the appropriate modality. While proton therapy planning and deliver is more complex than photon-based treatments, multicenter clinical outcomes have demonstrated similar disease control rates with that of IMRT or 3DCRT [95]. Furthermore, risks of pneumonitis have been extremely low [96], and there can be improved cardiac sparing [97]. Proton therapy may also be helpful in other situations including relapsed and refractory patients that require higher doses of radiation, when the disease involves the axilla, due to the ability to spare the breasts with posterior fields, and in pediatric HL, where the risk of second cancers is highest. Fig. 9.6 shows representative colorwash dose distributions for the same patient across different radiation treatment approaches. IMRT), and ISRT using proton therapy (ISRT PT) (Courtesy of Brad Hoppe, MD MPH, University of Florida, United States of America) 9 Principles of Radiation Therapy for Hodgkin Lymphoma 9.8 ommon Side Effects C and Supportive Care During Radiation Therapy The side effects of RT depend on the irradiated volume, dose administered, and technique employed. They are also influenced by the extent and type of prior chemotherapy, if any, and by the patient’s age, habits, and presence of intercurrent disease. Most of the information that we use today to estimate risk of RT is derived from strategies that used radiation alone, with larger treatment volumes and higher doses. As noted previously, field sizes have been reduced and doses decreased, and other technological advances have all drastically reduced the radiation exposure to the OARs. It is thus misleading to inform patients of risks of RT using information from RT of the past as this is no longer practiced. It is critical to remember that most of the data of long-term complications associated with RT and particularly second solid tumors and coronary heart disease were reported from databases of patients with HL treated more than 25 years ago. It is also important to note that we have very limited long-term follow-up data on patients with HL who were treated with chemotherapy alone. 9.8.1 Common Acute Side Effects Radiation, in general, may cause fatigue, and areas of the irradiated skin may develop mild sun exposure-like dermatitis. The acute side effects of irradiating the full neck and portions of the mouth include dryness, change in taste, and pharyngitis. Patients who are treated to the neck and mediastinum may also develop mild dysphagia and esophagitis, which is self-limited. With the doses and techniques of irradiation currently employed in HL, all of these side effects are usually mild and transient. The main potential side effects of subdiaphragmatic irradiation are loss of appetite, nausea, and increased bowel frequency. Again, these reactions are usually mild and can be minimized with standard antiemetic medications. 9.8.2 193 Uncommon Early Side Effects Lhermitte sign: Less than 3% of patients who have treatment that includes long lengths of the spinal cord may note an electric shock sensation radiating down the backs of both legs when the head is flexed (Lhermitte sign) 6 weeks to 3 months after mantle-field RT. Possibly secondary to transient demyelination of the spinal cord, Lhermitte sign resolves spontaneously after a few months and is not associated with late or permanent spinal cord damage. The risk is likely increased in the presence of prior neurotoxic chemotherapy such as vincristine or vinblastine. Pneumonitis and pericarditis: During the same period, radiation pneumonitis and/or acute pericarditis may occur in <3% of patients; these side effects occur more often in those who have extensive mediastinal disease. Both inflammatory processes have become rare with modern radiation techniques. The consideration and discussion of potential late side effects and complications of both RT and chemotherapy are of prime importance. A more complete discussion is detailed in Chap. 20. 9.8.3 upportive Care During S Treatment It is important to prepare the patient for the potential side effects of RT, and in addition to physician-led discussion, many organizations and cancer centers also provide written patient information regarding RT for lymphomas. Since some level of xerostomia may be associated with RT that involves the upper neck and/or lower mandible and mouth, attention to dental care is advised. If dryness is a concern, it is advised to arrange for a consultation with a dental expert for overall dental evaluation and consideration of mouth guards (from scatter) and/or supplemental fluoride treatment during and after RT. Soreness of the throat and mild-to-moderate difficulty of swallowing solid and dry food may also occur during neck irradiation, with onset at a J. Yahalom et al. 194 dose of approximately 20 Gy. These side effects are almost always mild, self-limited, and subside shortly after completion of RT. Skin care with hydrating lotion and sunscreen is advised for all patients undergoing RT. Temporary hair loss is expected in irradiated areas, and recovery is generally observed after several months. 9.8.4 Follow-Up After Treatment We normally recommend a first post-RT followup visit 6 weeks after the end of treatment and obtain post-RT baseline blood count, standard biochemistry tests, as well as TSH levels (if there was neck irradiation) and lipid profile (if applicable) at that visit. Follow-up imaging studies normally commence 3 months after completion of treatment. Patients treated with radiation therapy alone for NLPHL should have a posttreatment PET scan to confirm a complete response. Other follow-up studies are included in the NCCN guidelines for HL [2]. References 1. Lebow F (1996) Refining the management of Hodgkin’s disease. Oncology Times 1996:63 2. Hoppe RT, Advani R, Ai WZ et al (2018) National comprehensive cancer network guidelines: Hodgkin lymphoma, version 3.2018 3. Yahalom J (2009) Role of radiation therapy in Hodgkin’s lymphoma. Cancer J 15:155–160 4. Pusey W (1902) Cases of sarcoma and of Hodgkin’s disease treated by exposures to x-rays: a preliminary report. JAMA 38:166–169 5. Senn N (1903) Therapeutical value of roentgen ray in treatment of pseudoleukemia. N Y Med J 77:665–668 6. Gilbert R (1925) La roentgentherapie de la granulomatose maligne. J Radiol Electrol 9:509–514 7. Peters M (1950) A study in survivals in Hodgkin’s disease treated radiologically. Am J Roentgenol 63:299–311 8. Kaplan H (1962) The radical radiotherapy of Hodgkin’s disease. Radiology 78:553–561 9. Specht L, Yahalom J, Illidge T et al (2014) Modern radiation therapy for Hodgkin lymphoma: field and dose guidelines from the international lymphoma radiation oncology group (ILROG). Int J Radiat Oncol Biol Phys 89(4):854–862. https://doi.org/10.1016/j. ijrobp.2013.05.005 10. Girinsky T, van der Maazen R, Specht L et al (2006) Involved-node radiotherapy (INRT) in patients with 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. early Hodgkin lymphoma: concepts and guidelines. Radiother Oncol 79:270–277 Hodgson DC, Dieckmann K, Terezakis S et al (2015) Implementation of contemporary radiation therapy planning concepts for pediatric Hodgkin lymphoma: guidelines from the international lymphoma radiation oncology group. Pract Radiat Oncol 5(2):85–92 Brentuximab vedotin and combination chemotherapy in treating children and young adults with stage IIB or Stage IIIB-IVB Hodgkin lymphoma. (First posted June 18, 2014, last updated March 12, 2019). ClinicalTrials.gov Identifier: NCT02166463 Nogova L, Reineke T, Eich HT et al (2005) Extended field radiotherapy, combined modality treatment or involved field radiotherapy for patients with stage IA lymphocyte-predominant Hodgkin’s lymphoma: a retrospective analysis from the German Hodgkin study group (GHSG). Ann Oncol 16(10):1683–1687 Wirth A, Yuen K et al (2005) Long-term outcome after radiotherapy alone for lymphocyte-predominant Hodgkin lymphoma: a retrospective multicenter study of the Australasian radiation oncology lymphoma group. Cancer 104:1221–1229 Chen RC, Chin MS, Ng AK et al (2010) Early-stage, lymphocyte-predominant Hodgkin’s lymphoma: patient outcomes from a large, single-institution series with long follow-up. J Clin Oncol 28:136–141 Schlembach PJ, Wilder RB et al (2002) Radiotherapy alone for lymphocyte-predominant Hodgkin’s disease. Cancer J 8:377–383 Sasse S, Klimm B, Gorgen H et al (2012) Comparing long-term toxicity and efficacy of combined modality treatment including extended- or involved-field radiotherapy in early-stage Hodgkin’s lymphoma. Ann Oncol 23(11):2953–2959 Engert A, Plutschow A, Eich HT et al (2010) Reduced treatment intensity in patients with earlystage Hodgkin’s lymphoma. N Engl J Med 363(7): 640–652 Eich HT, Diehl V, Gorgen H et al (2010) Intensified chemotherapy and dose-reduced involved-field radiotherapy in patients with early unfavorable Hodgkin’s lymphoma: final analysis of the German Hodgkin study group HD11 trial. J Clin Oncol 28(27):4199–4206 Ferme C, Thomas J, Brice P et al (2017) ABVD or BEACOPPbaseline along with involved-field radiotherapy in early-stage Hodgkin lymphoma with risk factors: results of the European Organisation for Research and Treatment of Cancer (EORTC)-Groupe d’Etude des Lymphomes de l’Adulte(GELA) H9-U intergroup randomised trial. Eur J Cancer 81:45–55 Evens AM, Kostakoglu L (2014) The role of FDG- PET in defining prognosis of Hodgkin lymphoma for early-stage disease. Blood 124(23):3356–3364 Raemaekers JM, André MP, Federico M et al (2014) Omitting radiotherapy in early positron emission tomography-negative stage I/II Hodgkin lymphoma is associated with an increased risk of early relapse: clinical results of the preplanned interim analysis of the randomized EORTC/LYSA/FIL H10 trial. J Clin 9 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. Principles of Radiation Therapy for Hodgkin Lymphoma Oncol 32(12):1188–1194. https://doi.org/10.1200/ JCO.2013.51.9298 Radford J, Illidge T, Counsell N et al (2015) Results of a trial of PET-directed therapy for early-stage Hodgkin’s lymphoma. N Engl J Med 373(17):1598–1607 Illidge T et al (2018) Maximum tumour dimension at baseline is associated wth event-free survival in PET negative patients with stage IA/IIA Hodgkin lymphoma in the UK NCRI RAPID trial. International symposium on Hodgkin lymphoma (ISHL11), 26–29 Oct 2018, Cologne Andre MPE, Girinsky T, Federico M et al (2017) Early positron emission tomography response-adapted treatment in stage I and II Hodgkin lymphoma: final results of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol 35(16):1786–1794 Engert A et al (2018) Early-stage favorable HL: HD16. International symposium on Hodgkin lymphoma (ISHL11), 26–29 Oct 2018, Cologne Johnson P, Federico M, Kirkwood A et al (2016) Adapted treatment guided by interim PET-CT scan in advanced Hodgkin’s lymphoma. New Engl J Med 374(25):2419–2429 Meyer RM, Gospodarowicz MK, Connors JM et al (2012) ABVD alone versus radiation-based therapy in limited-stage Hodgkin’s lymphoma. N Engl J Med 366(5):399–408 Dann EJ, Bairey O, Bar-Shalom R et al (2017) Modification of initial therapy in early and advanced Hodgkin lymphoma, based on interim PET/CT is beneficial: a prospective multicenter trial of 355 patients. Br J Haematol 178(5):709–718 Straus DJ, Jung SH, Pitcher B et al (2018) CALGB 50604: a risk-adapted treatment of nonbulky early-stage Hodgkin lymphoma based on interim PET. Blood 132(10):1013–1021 Herbst C, Rehan FA et al (2009) Combined modality treatment improves tumor control and overall survival in patients with early stage Hodgkin lymphoma: a systematic review. Haematologica 95:494 Blank O, von Tresckow B, Monsef I et al (2017) Chemotherapy alone versus chemotherapy plus radiotherapy for adults with early stage Hodgkin lymphoma. Cochrane Database Syst Rev 4:CD0071010 Loeffler M, Diehl V et al (1997) Dose-response relationship of complementary radiotherapy following four cycles of combination chemotherapy in intermediate-stage Hodgkin’s disease. J Clin Oncol 15:2275–2287 Skoetz N, Trelle S, Rancea M et al (2013) Effect of initial treatment strategy on survival of patients with advanced-stage Hodgkin’s lymphoma: a systematic review and network meta-analysis. Lancet Oncol 14(10):943–952 Aleman BM, Raemaekers JM et al (2003) Involved- field radiotherapy for advanced Hodgkin’s lymphoma. N Engl J Med 348:2396–2406 Laskar S, Gupta T et al (2004) Consolidation radiation after complete remission in Hodgkin’s disease following six cycles of doxorubicin, bleomycin, vinblastine, 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 195 and dacarbazine chemotherapy: is there a need? J Clin Oncol 22:62–68 Johnson PWM, Sydes MR, Hancock BW et al (2010) Consolidation radiotherapy in patients with advanced Hodgkin’s lymphoma: survival data from the UKLG LY09 randomized controlled trial. J Clin Oncol 28:3352–3359 Engert A, Haverkamp H, Kobe C et al (2012) Reduced- intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin’s lymphoma (HD15 trial): a randomised, open-label, phase 3 non- inferiority trial. Lancet 379(9828):1791–1799 Gallamini A, Tarella C, Viviani S et al (2018) Early chemotherapy intensification with escalated BEACOPP in patients with advanced-stage Hodgkin lymphoma with a positive interim positron emission tomography/computed tomography scan after two ABVD cycles: long-term results of the GITIL/FIL HD 0607 trial. J Clin Oncol 36(5):454–462 Press OW, Li H, Schoder H et al (2016) US intergroup trial of response-adapted therapy for stage III to IV Hodgkin lymphoma using early interim Flurodeoxygluose-positron emission tomography imaging: southwest oncology group S0816. J Clin Oncol 34(17):2020–2027 Ha CS et al (2018) Potential impact of consolidation radiation therapy for advanced Hodgkin lymphoma: a secondary modeling of SWOG S0816 with receiver operating characteristic analysis. American Society of hematology annual meeting, 1–4 Dec San Diego, CA Poen JC, Hoppe RT et al (1996) High-dose therapy and autologous bone marrow transplantation for relapsed/refractory Hodgkin’s disease: the impact of involved field radiotherapy on patterns of failure and survival. Int J Radiat Oncol Biol Phys 36:3–12 Biswas T, Culakova E, Friedberg JW et al (2012) Involved field radiation therapy following high dose chemotherapy and autologous stem cell transplant benefits local control and survival in refractory or recurrent Hodgkin lymphoma. Radiother Oncol 103(3):367–372 Levis M, Piva C, Filippi AR et al (2017) Potential benefit of involved-field radiotherapy for patients with relapsed-refractory Hodgkin’s lymphoma with incomplete response before autologous stem cell transplantation. Clin Lymphoma Myeloma Leuk 17(1):14–22 Yahalom J, Gulati SC et al (1993) Accelerated hyperfractionated total-lymphoid irradiation, high-dose chemotherapy, and autologous bone marrow transplantation for refractory and relapsing patients with Hodgkin’s disease. J Clin Oncol 11:1062–1070 Moskowitz CH, Nimer SD et al (2001) A 2-step comprehensive high-dose chemoradiotherapy second-line program for relapsed and refractory Hodgkin’s disease: analysis by intent to treat and development of a prognostic model. Blood 97:617–623 Moskowitz CH, Kewalramani T et al (2004) Effectiveness of high dose chemoradiotherapy and J. Yahalom et al. 196 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. autologous stem cell transplantation for patients with biopsy-proven primary refractory Hodgkin’s disease. Br J Haematol 124:645–652 Rimner A, Lovie S, Hsu M et al (2017) Accelerated total lymphoid irradiation-containing salvage regimen for patietns with refractory and relapsed Hodgkin lymphoma: 20 years of experience. Int J Radiat Oncol Biol Phys 97(5):1066–1076 Goodman KA, Riedel E et al (2008) Long-term effects of high dose chemotherapy and radiation for relapsed and refractory Hodgkin’s lymphoma. J Clin Oncol 26:5240–5247 Constine LS, Yahalom J, Ng AK et al (2018) The role of radiation therapy in patients with relapse and refractory Hodgkin lymphoma: guidelines from the international lymphoma radiation oncology group. Int J Radiat Oncol Biol Phys 100(5):1100–1118 Yahalom J, Mauch P (2002) The involved field is back: issues in delineating the radiation field in Hodgkin’s disease. Ann Oncol 13(Suppl 1):79–83 Kaplan HS, Rosenberg SA (1966) The treatment of Hodgkin’s disease. Med Clin North Am 50:1591–1610 ICRU. International Commission on Radiation Units and Measurements (1999) Prescribing, recording, and reporting photon therapy. Supplement to ICRU report 50. ICRU report 62 Girinsky T, Specht L, Ghalibafian M et al (2008) The conundrum of Hodgkin lymphoma nodes: to be or not to be included in the involved node radiation fields. The EORTC-GELA lymphoma group guidelines. Radiother Oncol 88:202–210 Maraldo MV, Aznar MC, Vogelius IR et al (2013) Involved node radiotherapy: an effective alternative in early stage Hodgkin lymphoma. Int J Radiat Oncol Biol Phys 85:1057–1065 Paumier A, Ghalibafian M, Beaudre A et al (2011) Involved-node radiotherapy and modern radiation treatment techniques in patients with Hodgkin lymphoma. Int J Radiat Oncol Biol Phys 80:199–205 Pinnix CC, Smith GL, Milgrom S et al (2015) Int J Radiat Oncol Biol Phys 92(1):175–182 Van Nimwegen FA, Schaapveld M, Cutter DJ et al (2016) Radiation dose-response relationship for risk of coronary heart disease in survivors of Hodgkin lymphoma. J Clin Oncol 34(3):235–243 Bates JE, Howell RM, Liu Q et al (2019) Therapy- related cardiac risk in childhood cancer survivors: an analysis of the childhood cancer survivor study, JCO1801764. J Clin Oncol 2019. https://doi. org/10.1200/JCO/18/01764 Hoppe BS, Bates JE, Mendenhall NP et al (2019) The meaningless meaning of mean heart dose in mediastinal lymphoma in the modern radiation therapy Era. Pract Radiat Oncol pii:s1879– 8500(19)30279–6. https://doi.org/10.1016/j.prro.2019. 09.015 PMID:31586483 Cutter DJ, Schaapveld M, Darby SC et al (2015) Risk of valvular heart disease after treatment for Hodgkin lymphoma. J Natl Cancer Inst 23:107(4) 62. Cella L, Conson M, Caterino M et al (2012) Thyroid V30 predicts radiation-induced hypothyroidism in patients treated with sequential chemo-radiotherapy for Hodgkin’s lymphoma. Int J Radiat Oncol Biol Phys 82(5):1802–1808 63. Travis LB, Hill DA, Dores GM et al (2003) Breast cancer following radiotherapy and chemotherapy among young women with Hodgkin disease. JAMA 290(4):465–475 64. Travis LB, Gospodarowicz M, Curtis RE et al (2002) Lung cancer following chemotherapy and radiotherapy for Hodgkin’s disease. J Natl Cancer Inst 94(3):182–192 65. Tukenova M, Guibout C, Hawkins M et al (2011) Radiaiton therapy and late mortality from second sarcoma, carcinoma, and hematological malignancies after a solid cancer in childhood. Int J Radiat Oncol Biol Phys 80(2):339–346 66. Bhatti P, Veiga LH, Ronckers CM et al (2010) Risk of second primary thyroid cancer after radiotherapy for a childhood cancer in a large cohort study: an update from the childhood cancer survivor study. Radiat Res 174(6):741–752 67. Nivolumab and Brentuximab vedotin in treating older patients with untreated Hodgkin lymphoma. (First posted May 2, 2016, last updated January 14, 2019). ClinicalTrials.gov Identifier: NCT02758717 68. Brentuximab vedotin and nivolumab in treating participants with early stage classic Hodgkin lymphoma. (First posted October 19, 2018, last updated January 16, 2019). ClinicalTrials.gov Identifier: NCT03712202 69. Kumar A, Casulo C, Yahalom J et al (2016) Brentuximab vedotin and AVD followed by involved- site radiotherapy in early stage, unfavorable risk Hodgkin lymphoma. Blood 128(11):1458–1464 70. Yang JC et al (2018) Brentuximab vedotin and AVD chemotherapy followed by reduced dose/volume radiotherapy in patients with early stage, unfavorable Hodgkin lymphoma. International symposium on Hodgkin lymphoma (ISHL11), 26–29 Oct, Cologne 71. Duhmke E, Franklin J et al (2001) Low-dose radiation is sufficient for the noninvolved extended-field treatment in favorable early-stage Hodgkin’s disease: long-term results of a randomized trial of radiotherapy alone. J Clin Oncol 19:2905–2914 72. Duhmke E, Diehl V et al (1996) Randomized trial with early-stage Hodgkin’s disease testing 30 Gy vs. 40 Gy extended field radiotherapy alone. Int J Radiat Oncol Biol Phys 36:305–310 73. Prosnitz LR, Farber LR, Fischer JJ et al (1976) Long term remissions with combined modality therapy for advanced Hodgkin’s disease. Cancer 37(6):2826–2833 74. Donaldson SS, Link MP (1987) Combined modality treatment with low-dose radiation and MOPP chemotherapy for children with Hodgkin’s disease. J Clin Oncol 5:742–749 75. Dharmarajan KV, Friedman DL, Schwartz CL et al (2015) Patterns of relapse from a phase 3 study 9 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. Principles of Radiation Therapy for Hodgkin Lymphoma of response-based therapy for intermediate-risk Hodgkin lymphoma (AHOD0031): a report from the Children’s Oncology Group. Int J Radiat Oncol Biol Phys 92(1):60–66 Ferme C, Eghbali H et al (2007) Chemotherapy plus involved-field radiation in early-stage Hodgkin’s disease. N Engl J Med 357:1916–1927 Sasse S, Brockelmann PJ, Goergen H et al (2017) Long-term follow-up of contemporary treatment in early-stage Hodgkin lymphoma: updated analyses of the German Hodgkin study group HD7, HD8, HD10, and HD11 trials. J Clin Oncol 35(18):1999–2007 Hodgson DC, Koh ES et al (2007) Individualized estimates of second cancer risks after contemporary radiation therapy for Hodgkin lymphoma. Cancer 110:2576–2586 Kuttesch JF Jr, Wexler LH et al (1996) Second malignancies after Ewing’s sarcoma: radiation dose- dependency of secondary sarcomas. J Clin Oncol 14:2818–2825 Koontz B, Kirkpatrick J et al (2006) Combined modality therapy versus radiotherapy alone for treatment of early stage Hodgkin disease: cure versus complications. J Clin Oncol 24:605–611 Salloum E, Doria R et al (1996) Second solid tumors in patients with Hodgkin’s disease cured after radiation or chemotherapy plus adjuvant low-dose radiation. J Clin Oncol 14:2435–2443 Zhou R, Ng A, Constine LS et al (2016) A comparative evaluation of normal tissue doses for patients receiving radiaiton therapy for Hodgkin’s lymphoma on the childhood Cancer survivor study and recent Children’s oncology group trials. Int J Radiat Oncol Biol Phys 95(2):707–711 Arakelyan N, Jais J-P, Delwall V et al (2010) Reduced versus full doses of irradiation after 3 cycles of combined doxorubicin, bleomycin, vinblastine, and dacarbazine in early stage Hodgkin lymphomas. Cancer 116:4054–4062 Tseng YD, Cutter DJ, Plastaras JP et al (2017) Evidence-based review on the use of proton therapy in lymphoma from the particle therapy cooperative group (PTCOG) lymphoma subcommittee. Int J Radiat Oncol Biol Phys 99(4):825–842 Voong KR, McSpadden K, Pinnix CC et al (2014) Radiat Oncol 9(94):1–9 Milgrom SA, Chi PCM, Pinnix CC, et al. IJROBP 2017 99(2) S61 Filippi AR, Ragona R, Piva C et al (2015) Optimized volumetric arc therapy versus 3D-CRT for early stage mediastinal Hodgkin lymphoma without axil- 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 197 lary involvement: a comparison of second cancers and heart disease risk. Int J Radiat Oncol Biol Phys 92(1):161–168 Levis M, De Luca V, Fiandra C et al (2018) Plan optimization for mediastinal radiotherapy: estimation of coronary arteries motion with ECG-gated cardiac imaging and creation of compensatory expansion margins. Radiother Oncol 127(3):481–486 Girinsky T, Pichenot C, Beaudre A et al (2006) Is intensity-modulated radiotherapy better than conventional radiation treatment and three-dimensional conformal radiotherapy for mediastinal masses in patients with Hodgkin’s disease, and is there a role for beam orientation optimization and dose constraints assigned to virtual volumes? Int J Radiat Oncol Biol Phys 64(1):218–226 Petersen PM, Azxnar MC, Berthelsen AK et al (2015) Acta Oncol 54(1):60–66 Charpentier AM, Conrad T, Sykes J et al (2014) Active breathing control for patients receiving mediastinal radiaiton therapy for lymphoma: impact on normal tissue dose. Pract Radiat Oncol 4(3): 174–180 Hoppe BS, Mendenhall NP, Louis D et al (2017) Comparing breath hold and free breathing during intensity-modulated radiation therapy and proton therapy in patients with mediastinal Hodgkin lymphoma. Int J Part Ther 3(4):492–496 Paumier A, Ghalibafian M, Gilmore J et al (2012) Dosimetric benefits of intensity-modulated radiotherapy combined with the deep-inspiration breath-hold technique in patients with mediastinal Hodgkin’s lymphoma. Int J Radiat Oncol Biol Phys 82(4):1522–1527 Dabaja BS, Hoppe BS, Plastaras JP et al (2018) Proton therapy for adults with mediastinal lymphomas: the international lymphoma radiation oncology group guidelines. Blood 132(16):1635–1646 Hoppe BS, Hill-Kayser CE, Tseng YD et al (2017) Consolidative proton therapy after chemotherapy for patients with Hodgkin lymphoma. Ann Oncol 28(9):2179–2184 Nanda R, Flampouri S, Mendenhall NP et al (2017) Pulmonary toxicity following proton therapy for thoracic lymphoma. Int J Radiat Oncol Biol Phys 99(2):494–497 Hoppe BS, Flampouri S, Su Z et al (2012) Effective dose reduction to cardiac structures using protons compared with 3DCRT and IMRT in mediastinal Hodgkin lymphoma. Int J Radiat Oncol Biol Phys 84(2):449–455 Principles of Chemotherapy in Hodgkin Lymphoma 10 David Straus and Mark Hertzberg Contents 10.1 Historical Introduction 10.2 hemotherapy Applied to Advanced-Stage Hodgkin C Lymphoma: Theories and Practice Classes of Active Classical Agents in HL Polychemotherapy: Models and Comparative Clinical Studies MOPP and Derivatives ABVD and Derivatives The Dose/Response Relationship: Norton and Simon Model Sustained/Weekly Regimens Escalated-Dose Regimens High-Dose Treatment and Autologous Stem Cell Transplantation as Part of Initial Therapy Risk-Adapted Regimens Based on PET Incorporation of Antibody-Drug Conjugate in Primary Treatment of Advanced-Stage cHL 10.2.1 10.2.2 10.2.2.1 10.2.2.2 10.2.2.3 10.2.2.4 10.2.2.5 10.2.2.6 10.2.2.7 10.2.2.8 199 200 200 201 201 205 206 207 208 209 210 213 10.3.1 hemotherapy Treatment for Recurrent and Refractory Hodgkin C Lymphoma New Systemic Treatments 213 213 10.4 Conclusions 214 10.3 References 214 10.1 D. Straus (*) Division of Hematologic Malignancies, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA e-mail: strausd@mskcc.org M. Hertzberg Department of Haematology, Prince of Wales Hospital, Randwick, NSW, Australia e-mail: mark.hertzberg@sesiahs.health.nsw.gov.au Historical Introduction Hodgkin lymphoma (HL) was the malignant disease for which the possibility of cure with combination chemotherapy in the majority of patients was first realized. As such it has provided a model upon which studies in many other types of malignancy have been based, and it is interesting to follow the trajectory of knowledge from early single-agent work through combinations, © Springer Nature Switzerland AG 2020 A. Engert, A. Younes (eds.), Hodgkin Lymphoma, Hematologic Malignancies, https://doi.org/10.1007/978-3-030-32482-7_10 199 D. Straus and M. Hertzberg 200 combined modalities, increasing complexity, and, most recently, selective de-escalation. Patients with advanced disease represent a minority of those affected by HL. However, these patients represent the group in which the development and effects of chemotherapy are most readily appreciated, because the role of radiation therapy is markedly less than in patients with localized disease. As early as 1942, four patients with HL were treated with nitrogen mustard by Wilkinson and Fletcher at Manchester Royal Infirmary, although a military embargo prevented the dissemination of this information [1]. Similar considerations are applied to the bombing of the ship “USS Liberty” on December 3, 1943, in Bari, and the hematological consequences of a nitrogen mustard gas leak among the survivors. Cornelius Rhoads, an American cancer researcher, was involved in their care and understood from his observations of the effects on the bone marrow and lymphoid tissue that nitrogen mustard derivatives might be effective against lymphoid and hematological malignancies [2, 3]. In 1958, another alkylating agent, cyclophosphamide, proved effective in non-Hodgkin lymphoma (NHL) [4]. Shortly after this, vinblastine was first shown to be an effective drug in HL, as was vincristine. Although encouraging, the early results of chemotherapy were modest, with most responses short-lived after corticosteroids and alkylating and spindle cell agents [5–7]. There was a prevalent view that only extensive irradiation could yield complete cures [8, 9]. One of the first modern randomized studies was the EORTC H1 trial, which investigated whether “adjuvant” chemotherapy (weekly vinblastine for 2 years) could improve the results over radiotherapy alone [10]. A durable advantage was seen in the chemotherapy arm for relapse-free survival (RFS: at 15 years 60% vs. 38%; P < 0.001) although more than 50% of patients with mixed-cellularity histology developed recurrences [11]. To reduce the relapse rate, irradiation was extended to infradiaphragmatic nodal and spleen areas. Singleagent or doublet chemotherapy was added after radiotherapy, but no immediate attempt was made to use polychemotherapy, based upon the idea that the cure rate would depend upon the adequacy of irradiation [12, 13]. Two factors gradually undermined the dominance of strict pathological delineation and extensive irradiation as the basis of curative therapy in HL: the advent of accurate cross-sectional imaging by computed tomographic (CT) scanning and the recognition that relapses after irradiation alone had minimal impact on survival owing to the efficacy of salvage chemotherapy [14]. With the development of four-drug combination therapy, which for the first time resulted in cures for advanced HL without the need for irradiation, the transition to systemic therapy began in earnest. 10.2 Chemotherapy Applied to Advanced-Stage Hodgkin Lymphoma: Theories and Practice 10.2.1 C lasses of Active Classical Agents in HL (Table 10.1) Almost every class of chemotherapy drug has been shown to have some efficacy in HL, with the possible exception of the antimetabolite drugs such as 5-fluorouracil [15]. The original combination treatments were based upon evidence of single-agent activity among alkylating agents, vinca alkaloids, corticosteroids, and the hydralazine monoamine oxidase inhibitor procarbazine. All of these produced response rates of over 50% when used singly in patients not previously exposed to multiagent chemotherapy (Table 10.1). Later entrants to this field included the antibiotic drugs doxorubicin and bleomycin, the nitrosoureas and dacarbazine, and the podophyllotoxins, all of which showed appreciable single-agent activity after prior combination regimens. More recently, newer cytotoxics such as gemcitabine have been introduced, often in combination with platinum drugs, and found to produce significant response rates in recurrent disease. In 2011, brentuximab vedotin, an antibody-drug conjugate, was approved in the USA and conditionally in Europe 10 Principles of Chemotherapy in Hodgkin Lymphoma Table 10.1 Single-agent activity of cytotoxic drugs in Hodgkin lymphoma [15] Complete Overall response rate response rate (%) (%) Drug Single agents tested before combination chemotherapy Alkylating agents Chlorambucil 61 16 Mustine 63 13 Cyclophosphamide 54 12 Vinca alkaloids Vinblastine 68 30 Vincristine 60 36 Agents mainly tested after prior multiagent therapy Dacarbazine 56 6 Nitrosoureas Carmustine 44 5 Lomustine 48 12 Antibiotics Doxorubicin 30 5 Bleomycin 38 6 Podophyllotoxin Etoposide 27 6 Antimetabolite Gemcitabine 22 0 Antibody-drug conjugate Brentuximab vedotin 75 34 201 feature of the malignant cells themselves or their associated inflammatory infiltrate, which may be critical to sustaining them. The development of combination therapies has been based mainly upon the use of agents with non-overlapping toxicity as far as possible, and as cure rates have risen, the emphasis has fallen increasingly upon avoiding long-term side effects. The most important among these are infertility and myelodysplasia, mainly caused by the alkylating agents; pulmonary fibrosis caused by bleomycin and nitrosoureas; and cardiomyopathy related to anthracyclines, a risk increased by the concomitant use of mediastinal radiotherapy. 10.2.2 Polychemotherapy: Models and Comparative Clinical Studies (Tables 10.2 and 10.3) 10.2.2.1 MOPP and Derivatives Combination chemotherapy was first attempted clinically in childhood acute lymphoblastic leukemia by Jean Bernard [18], who designed two doublets of cortisone-methotrexate and prednisone- vincristine, at the same time as pursuing work on chemotherapy for HL. Lacher and Durant were the first to use doublet combinafor treatment of relapsed or refractory HL after tion chemotherapy in HL with vinblastine and autologous stem cell transplantation (ASCT) or chlorambucil [19]. At the NCI, Freireich, Frei, after at least two combination chemotherapy regi- and Katon added 6-mercaptopurine into the more mens in patients who are not transplant candi- effective VAMP (vincristine, amethopterin, merdates. Approval was granted on the basis of an captopurine, and prednisone) regimen [7]. This overall response (OR) rate of 75% and a complete led on to MOMP (cyclophosphamide, vincrisresponse (CR) rate of 34% in a phase 2 trial in 102 tine, methotrexate, and prednisone) and MOPP HL patients relapsed after or refractory to ASCT, (mechlorethamine, vincristine, procarbazine, response rates approximately twice as high as prednisone), developed by DeVita and Carbone, those reported for other single agents [16]. This also at the NCI [20, 21]. Some of the critical feaantibody-drug conjugate attaches an anti-CD30 tures of success were prolonged treatment antibody to a potent antimicrotubular agent, (6 months, more than any other regimen at the monomethyl auristatin (MMAE), by a protease time); the use of each drug at “optimal” dose and cleavable linker. MMAE binds to tubulin and dis- schedule with a sliding scale for dose adjustment rupts the microtubule network, inducing cell cycle according to marrow suppression; an interval of arrest and apoptosis, a mechanism of action simi- 2 weeks for recovery of normal tissue (marrow, lar to those for vincristine and vinblastine [17]. GI epithelium), ideally before HL recovery; and It is clear that HL is broadly sensitive to phase- treatment with curative intent rather than palliaspecific, cycle-specific, and non-cycle-specific tion. MOPP provided an 80% response rate and agents, although it is less clear whether this is a long-term disease-free (DFS) and overall survival D. Straus and M. Hertzberg 202 Table 10.2 Chemotherapy regimens designed for advanced Hodgkin lymphoma Drugs Four-drug regimens MOPP Mechlorethamine Vincristine Procarbazine Prednisolone MVPP Mechlorethamine Vinblastine Procarbazine Prednisolone ChlVPP Chlorambucil Vinblastine Procarbazine Prednisolone COPP Cyclophosphamide Vinblastine Procarbazine Prednisolone ABVD Doxorubicin Bleomycin Vinblastine Dacarbazine Hybrid regimens MOPP/ABV Mechlorethamine Vincristine Procarbazine Prednisolone Doxorubicin Bleomycin Vinblastine ChlVPP/EVA Chlorambucil Vincristine Procarbazine Etoposide Prednisolone Doxorubicin Vinblastine BEACOPP baseline Bleomycin Etoposide Doxorubicin Cyclophosphamide Vincristine Dose, mg/m2 Route 6 1.4 (cap 2 mg) 100 40 Iv Iv Po Po 6 6 (cap 10 mg) 100 40 Iv Iv Po Po 6 (cap 10 mg) 6 (cap 10 mg) 100 40 Po Iv Po Po 650 6 100 40 Iv Iv Po Po 25 10 iu/m2 6 375 Iv Iv Iv Iv 6 1.4 100 40 35 10 iu/m2 6 Iv Iv Po Po Iv Iv Iv 6 (cap 10 mg) 1.4 (cap 2 mg) 90 75 50 50 6 (cap 10 mg) Po Iv Po Po Po Iv Iv 10 iu/m2 100 25 650 1.4 (cap 2 mg) Iv Iv Iv Iv Iv Schedule q. 28 days d1 and 8 d1 and 8 d1–14 d1–14 q. 42 days d1 and 8 d1 and 8 d1–14 d1–14 q. 28 days d1–14 d1 and 8 d1–14 d1–14 q. 28 days d1 and 8 d1 and 8 d1–14 d1–14 q. 28 days d1 and 15 d1 and 15 d1 and 15 d1 and 15 q. 28 days d1 d1 d1–7 d1–14 d8 d8 d8 q. 28 days d1–7 d1 d1–7 d1–5 d1–7 d8 d8 q. 21 days d8 d1–3 d1 d1 d8 10 Principles of Chemotherapy in Hodgkin Lymphoma 203 Table 10.2 (continued) Drugs Procarbazine Prednisolone Escalated regimens Escalated BEACOPP Bleomycin Etoposide Doxorubicin Cyclophosphamide Vincristine Procarbazine Prednisolone G-CSF BEACOPP-14 Bleomycin Etoposide Doxorubicin Cyclophosphamide Vincristine Procarbazine Prednisolone G-CSF Weekly regimens Stanford V Doxorubicin Vinblastine Mechlorethamine Vincristine Bleomycin Etoposide Prednisolone VAPEC-B Doxorubicin Cyclophosphamide Etoposide Vincristine Bleomycin Prednisolone BV/AVD Brentuximab vedotin Doxorubicin Vinblastine Dacarbazine Dose, mg/m2 100 40 Route Po Po 10 iu/m2 200 35 1250 1.4 (cap 2 mg) 100 40 Iv Iv Iv Iv Iv Po Po Sc 10 iu/m2 100 25 650 1.4 (cap 2 mg) 100 80 Iv Iv Iv Iv Iv Po Po Sc 25 6 6 1.4 (cap 2 mg) 5 i.u./m2 60 40 Iv Iv Iv Iv Iv Iv Po 35 350 75–100 1.4 (cap 2 mg) 10 50 Iv Iv Iv Iv Iv Po 4-week cycle d1 and 15 d1 and 15 d1 d8 and 22 d8 and 22 d15 and 16 Daily to week 10 then taper 4-week cycle d1 and 15 d1 d15–20 d8 and 22 d8 and 22 Daily to week 6 then taper 1.2 mg/kg 25 6 375 Iv Iv Iv Iv d1 and 15 d1 and 15 d1 and 15 d1 and 15 (OS) of almost 50% and 40%, respectively [22]. The results have held up, and the 20-year analysis confirmed among 198 patients a CR rate of 81%, a 19% rate of induction failures, a 36% relapse rate, and a 54% mortality. Of the 106 deaths, 30 Schedule d1–7 d1–14 q. 28 days d8 d1–3 d1 d1 d8 d1–7 d1–14 d8–14 q. 14 days d8 d1–3 d1 d1 d8 d1–7 d1–7 d8–13 occurred in patients free of disease; among the 92 patients who survived (46%), only two had persistent HL [23]. These results have been reconfirmed in subsequent trials (Table 10.3) [24–27]. Although the rise in cures from HL can be D. Straus and M. Hertzberg 204 Table 10.3 Summary results of combination chemotherapy regimens used in first-line therapy of advanced Hodgkin lymphoma Regimen MOPP [22–25, 101] MVPP [38, 102, 103] ChlVPP [39, 104] ABVD [24, 47, 68, 69, 77, 78, 105] MOPP/ABVD alternating [24, 106, 107] COPP/ABVD alternating [62, 108] MOPP/ABV hybrid [47, 107, 109, 110] Stanford V [66–69] VAPEC-B [71] ChlVPP/EVA [71, 105] BEACOPP baseline [62] Escalated BEACOPP [62] BV/AVD [95] 5 year 5 year ≥7 year CR (%) EFS (%) OS (%) OS (%) 67–81 40–60 65–73 51–70 72–76 60 65–75 57–74 55–60 66 65 68–92 61–80 73–90 77 83–92 65–70 75–84 74 85 69 83 75 80–88 66–75 76–83 72 72–91 54–94 82–96 47 67 62 82–84 79 89 88 76 88 80 81–96 87 91 86 73 82a,b 97a 2 Years Modified PFS (time to disease progression, death, or modified progression) a b ascribed to multiple advances and not just the introduction of effective chemotherapy, the 1970 report convinced almost all groups treating HL to accept the inclusion of polychemotherapy (MOPP or MOPP derivatives) in the treatment strategy for localized as well as advanced disease. In almost all instances where a combined treatment was compared to irradiation alone, whether patients were staged or not with laparotomy, advantages in terms of response and disease- and relapse-free survival were observed when MOPP or a MOPP-derived chemotherapy was used [28]. Analysis of the results with MOPP has proven a fruitful source of information to design and interpret future studies. Thus, complete response was seen to be a prerequisite for sustained remission, and a high percentage of complete responses was correlated with higher survival rates. Capping the vincristine dose at 2 mg may have been detrimental to the results. Patient and initial disease characteristics were good predictors of outcome, with confirmation of the adverse prognostic significance of systemic “B” symptoms. Maintenance treatment with intermittent MOPP or carmustine did not appear beneficial [29]. In patients treated previously by irradiation and chemotherapy, MOPP was less well-tolerated and less effective [30]. Conversely, retreatment in relapsed patients whose initial remission lasted over a year proved efficient on the second occasion [31]. MOPP therapy carries consequences in terms of carcinogenicity, in particular with secondary acute myeloid leukemia (AML) [32, 33]. It is also responsible for impaired fertility in both men and women [34]. Immunosuppression related to the treatment, or to the underlying disease, brings risks of different types, in particular of opportunistic infection [35]. There were many attempts to improve upon these results. The three best-known MOPP- derived regimens have been MVPP, with vinblastine instead of vincristine; ChlVPP (chlorambucil, vinblastine, procarbazine, and prednisolone); and COPP, with an additional substitution of mechlorethamine, replaced by chlorambucil or cyclophosphamide (Tables 10.2 and 10.3). These alternatives have never undergone direct comparison, and historical controls are difficult to interpret. In addition, the proportion of patients who have also had radiotherapy varies considerably between series. For example, in the NCI series, 32/198 patients had been irradiated prior to MOPP, and 28/198 patients received total nodal irradiation (TNI) “to prevent recurrent disease in previously involved nodes” as consolidation after chemotherapy. MVPP, devised in the UK, proved easier to handle than MOPP (with less constipation and neurological toxicity), but was slightly more myelotoxic [36–38]. ChlVPP appeared more patient-friendly, inducing minimal nausea/vomiting, constipation or neurologic toxicity, and limited hematotoxicity, and the number of cycles could be adapted to the 10 Principles of Chemotherapy in Hodgkin Lymphoma response: a maximum of five beyond CR. The 66% OS rate in advanced HL was comparable to mustine-containing regimens, at lower toxic cost, for all of these acute toxicities, except myelosuppression [39, 40]. COPP is less myelotoxic than MOPP and is often used in children [41]. 205 HL. In 232 patients, a combined modality approach of three cycles before and after extensive irradiation yielded a CR rate of 80.7% after MOPP/radiotherapy and 92.4% after ABVD/ radiotherapy (P < 0.02). At 7 years follow-up, ABVD surpassed MOPP for freedom from progression (FFP) (80.8% vs. 62.8%; P < 0.002), 10.2.2.2 ABVD and Derivatives RFS (87.7% vs. 77.2%; P = 0.06), and OS (77.4% The ABVD regimen (doxorubicin, bleomycin, vs. 67.9%; P = 0.03). With longer follow-up, the vinblastine, and dacarbazine) was devised just disadvantages of MOPP in terms of fertility dam10 years after MOPP, in 1973, for intravenous- age and second myelodysplasia (MDS) and leuonly administration at fixed 2-week intervals. kemia were also more apparent. The final Like MOPP, ABVD was a combination of hema- establishment of ABVD as the favored regimen, totoxic and neurotoxic drugs. Both doxorubicin at least in North America, was based on two ranand vinblastine had been shown highly effective domized trials for advanced HL. In the first, in HL. The results with dacarbazine were numer- MOPP vs. ABVD vs. MOPP alternating with ous but possibly less convincing, and bleomycin ABVD were associated with 5-year failure-free was also felt to have considerable potential [10, survival rates of 50%, 61%, and 65%, respec42–45]. By comparison to MOPP, hematotoxicity tively. There was less toxicity with ABVD than after ABVD was predictable, noncumulative, and with MOPP or MOPP alternating with ABVD milder as a result of the intravenous dosing and and no significant difference in survival among short intervals. Further, ABVD was far less neu- the three regimens [24]. A second trial compared rotoxic. Bonadonna developed ABVD at the ABVD with a hybrid regimen, MOPP/ABV; Milan NCI with the intention: “to compare the 5-year failure-free survival rates were 63% and efficacy of ABVD with MOPP, and to demon- 66%, respectively. There was a greater incidence strate absence of cross-resistance between the of acute toxicity, myelodysplastic syndrome, and two regimens” [46]. The results of MOPP were leukemia for MOPP/ABV compared with well established and the potential of ABVD in ABVD. Again, there was no significant differterms of “alternative to MOPP to be used either ence in survival [47]. in MOPP failures or in sequential combination Currently, ABVD is considered by most inveswith MOPP” was clearly in the mind of the tigators as the standard chemotherapy for most authors, based on these very early results achieved patients with HL, with the possible exception of in 45 patients. No significant cardiac toxicity was high-risk patients with advanced disease and seen in this first series, probably because of the poor prognostic features. Reasons to avoid relatively small cumulative dose of doxorubicin ABVD relate to previous lung impairment and (6 cycles = 300 mg/m2), the short follow-up, and decreased left ventricular ejection fraction. the small numbers of patients. Conversely, bleo- Hematological toxicity is usually moderate, and mycin pulmonary toxicity was apparent from the ABVD may be delivered safely at full dose and outset, while the effects upon fertility were ini- on schedule to a non-selected average population tially overestimated through short observation of adult patients without the need to modify doses which did not take into account the reversal of in the presence of neutropenia [48]. The most fretemporary amenorrhea in some women. quent serious toxicity with ABVD is pulmonary It took a surprisingly long time for ABVD to fibrosis, which may be fatal [49]. The discontinube accepted as a standard of care, and it was ini- ation of bleomycin for toxicity during ABVD tially considered only as a salvage treatment in treatment does not appear to have an adverse MOPP failures. However, the Milan group under- effect on outcome, which calls into question the took a larger trial, comparing MOPP and ABVD importance of bleomycin in the ABVD regimen directly in patients with stage IIB, IIIA, and IIIB [47, 49–51]. This possibility has recently been 206 tested prospectively in a randomized study of patients showing a good early response to ABVD, where patients either continued all drugs, or AVD only [17, 52]. The results confirmed the excess toxicity associated with bleomycin, particularly reduced lung function and more instances of venous thromboembolism. There was no decrease in efficacy by omission of bleomycin from the last four cycles of treatment. 10.2.2.3 The Dose/Response Relationship: Norton and Simon Model Much of the thinking about how to maximize the cure rate in lymphoma has centered upon the relationship between dose and response to cytotoxic therapy. Theories of tumor cell ecology have suggested that as the mass of disease is reduced, the growth fraction may rise. This, together with the assumed selection of resistant subclones, underlies the idea that tumor eradication is dependent upon the delivery of treatment at adequate dose intensity early in a course of treatment. If doses are too small or too infrequent, the fractional cell kill might be expected to decline and allow the emergence of resistance [53]. Three prospective clinical trials have directly addressed the question of dose versus response using the same chemotherapy drugs in both arms. In the first-line treatment of advanced disease, a critical study, HD9, was performed by the German Hodgkin Study Group (GHSG), as detailed later, in which patients were randomized between the baseline BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) regimen and an escalated regimen, with the doses of doxorubicin, cyclophosphamide, and etoposide increased to 140%, 185%, and 200%, respectively. This resulted in an increase in freedom from treatment failure (FFTF) at 5 years from 76% to 87% (P < 0.01), which was translated into a small but significant improvement in survival on longer follow-up (80% vs. 86% at 10 years; P = 0.0053). This was at the cost of an increased risk of MDS and AML in the escalated arm, but at a frequency too low to reverse the D. Straus and M. Hertzberg gain in survival from better control of the lymphoma [54]. There are two randomized studies for recurrent disease which have yielded similar data on the dose-response relationship. The UK group compared the myeloablative BEAM (carmustine, etoposide, cytarabine, and melphalan) regimen to mini-BEAM, which uses the same drugs at nonmyeloablative doses. The high-dose treatment yielded superior PFS (P = 0.005), although the trial was closed with only 44 patients recruited and had insufficient power to demonstrate a survival advantage [55]. A study of similar design was conducted by the GHSG, and this too demonstrated superior FFTF at 3 years (55% for BEAM, 34% for nonmyeloablative dexa-BEAM, P = 0.019), although once again no survival difference could be demonstrated [56]. While there is good evidence for an overall dose-response relationship, there are several areas of continuing uncertainty. For example, it is not clear whether the dose of treatment over a whole course is the critical determinant of outcome, or whether initial dose intensity during the first weeks of treatment is more important. From retrospective analyses comparing outcomes to doses administered, it appears that the most influential factor is the total dose of treatment given, with some scope for compensating suboptimal early treatment by later escalation, a finding that may distinguish HL from many other malignancies [57–59]. Dose/Response Relationships and Treatment Tolerance: An Individual Characteristic? A dose response for both malignant and normal tissue toxicity is well-recognized, raising the question of whether the efficacy of tumor control can be related to toxic side effects, effectively using each subject as his or her own pharmacodynamic control. The GHSG explored hematotoxicity as a surrogate for pharmacological and metabolic heterogeneity, in relation to reduced systemic dose and disease control. Patients treated with various regimens in the HD6 trial (validated on two other cohorts) were retrospectively classified as showing WHO 10 Principles of Chemotherapy in Hodgkin Lymphoma grade l eukocytopenia of 0–2 and >2, respectively. Patients with a high hematological toxicity had a 5-year FFTF rate of 68% versus 47% for those with low toxicity, independent of the actual drug doses received [60]. No pretreatment pharmacokinetic parameters could be found to explain these observations; however, recent work from the French Study Group of the Adult Lymphoma (GELA) has explored polymorphisms in a population of HL patients that might determine anticancer agent metabolism. The UGT1A1 polymorphism has been identified as a possible candidate for influencing the metabolism of several anticancer drugs and patient outcomes [61]. Unfortunately, similar dose-response relationships are also seen for long-term toxicities, for example, infertility and secondary leukemias [62–64]. 10.2.2.4 Sustained/Weekly Regimens Pursuing the idea of increased dose intensity, several groups developed novel, brief duration regimens for the treatment of advanced HL. The rationale for the development of these regimens was, firstly, increased dose intensity of chemotherapy by reduction in the total duration of treatment but an increase in the number of different agents and, secondly, reduced cumulative doses of drugs responsible for long-term toxic effects, including alkylating agents, doxorubicin, and bleomycin. The PACEBOM, VAPEC-B, and Stanford V regimens were all designed to deliver weekly treatments, alternating between myelosuppressive and nonmyelosuppressive agents. The preliminary results from single-arm studies appeared promising, with high response and survival rates [65]. Unfortunately, the results of randomized trials did not confirm the early promise of these regimens. The Stanford V program developed from the close collaboration of radiotherapy and chemotherapy, endeavoring to minimize the use of each modality to achieve improved results with less toxicity. Initial chemotherapy was composed of the standard drugs from the MOPP/ABVD scheme (mechlorethamine, doxorubicin, bleomycin), plus etoposide, with dose intensity increased for better and earlier tumor response, while 207 cumulative doses, thought to be responsible for late toxicity (marrow, heart, lung), were reduced. The use of alkylating agents was limited in order to avert gonadal damage. The final scheme was an abbreviated 12-week program with radiotherapy started 2–4 weeks after chemotherapy, restricted to sites at higher risk for relapse (bulky sites), and delivered at 36 Gy, in order to reduce the incidence of late cardiopulmonary effects, and “mini-mantle” instead of mantle fields, sparing the axillae to decrease the risk of secondary breast carcinoma. The results of the initial Stanford V phase 2 approach were confirmed in the Eastern Cooperative Oncology Group (ECOG) E1492 study in 45 patients, of whom 87% received radiotherapy; FFP was 85% at 5 years, and OS was 96% with one death from HL and one from an M5 AML [66]. Later analysis confirmed these excellent results and the relative preservation of fertility in both women and men; no case of secondary MDS/leukemia or NHL had been registered at a 65 months median follow-up [67]. A randomized trial (Italian Lymphoma Group: ILL) compared Stanford V to mechlorethamine, vincristine, procarbazine, prednisone, epidoxorubicin, bleomycin, vinblastine, lomustine, doxorubicin, and vindesine (MOPPEBVCAD) and to ABVD as the standard in 355 patients with stage IIB–IV HL. In this trial, the Stanford V arm was inferior to the other two arms in terms of 5-year FFS (54% vs. 78% for ABVD and 81% for MOPPEBVCAD, respectively (P < 0.01) for comparison of Stanford V with the other two regimens) [68]. However, only 66% of patients in the Stanford V arm received irradiation, against 87% in the ECOG phase 2 study: this is important in a strategy that was originally designed to combine both modalities. The Stanford V program was also compared to ABVD in a large prospective trial run by the UK National Cancer Research Institute Lymphoma Group (NCRI) in 520 patients with stage IIB–IV HL. Results in the Stanford V and in the ABVD arm were similar for 5-year PFS and OS rates (76% and 90%, for ABVD; 74% and 92% for Stanford V, with radiotherapy administered in 53% and 73%, respectively) [69]. The North American Intergroup trial 208 led by ECOG (E2496) compared ABVD with IFRT only to bulky mediastinal sites with the combined modality Stanford V. There was no difference in response rates or in 5-year FFS or OS rates between the two arms of the trial. The relatively extensive use of radiotherapy required to achieve optimum results for weekly regimens makes them a less attractive choice for many patients: in the UK study, 73% of patients treated with Stanford V received consolidation radiotherapy, compared to 37% in the previous UK study using ABVD in a similar group of patients. In E2496, 75% of patients on the Stanford V regimen received radiation therapy, while 41% of those on ABVD had irradiation of bulky mediastinal sites [70]. The short 12-week duration of the Stanford V regimen has some appeal for patients and remains a reasonable approach for those with low-risk non-bulky disease, for whom limited or no irradiation is needed, but this is only a minority. The only other weekly regimen to be compared with a hybrid regimen in a randomized trial featured myelosuppressive (doxorubicin, cyclophosphamide, and etoposide) and relatively nonmyelosuppressive (vincristine and bleomycin) drugs given on an alternating weekly basis for 11 weeks: VAPEC-B. This regimen was compared to a hybrid ChlVPP-EVA schedule for advanced disease, was expected to still be significantly more myelosuppressive and to impair fertility, and showed inferior PFS for the weekly regimen in all but the best prognosis subgroup. Event-free survival at 5 years in newly diagnosed patients with advanced disease following the hybrid regimen was 78% versus 58% for VAPEC-B, which translated into better OS, at 89% versus 79% [71]. 10.2.2.5 Escalated-Dose Regimens In order to spare patients the acute gastrointestinal and hematologic toxicities, the original recommendation of the NCI to follow a “sliding scale” of dose adaptation for MOPP was gradually superseded by fixed doses at well-tolerated levels and intervals. Retrospective studies of MOPP and MVPP suggested that the cumulative dose, as much as frequency of administration or dose D. Straus and M. Hertzberg intensity, might determine the outcomes [25, 72]. These observations also appear to hold for ABVD [59], although all these studies are retrospective and need to be confirmed in a prospective study. The GHSG has pioneered the exploration of two levels of dose increment, in the conventional dose range, by reducing the length of treatment and adding etoposide to the standard regimen, COPP/ABVD [73]. Further intensification was carried out by increasing the myelosuppressive drug doses, with growth factor support. Both intensified regimens provided higher CR and FFTF and, crucially, statistically higher OS rates as compared to standard COPP/ABVD [54]. The early effects of dose intensification were maintained in the long-term results at 10 years: FFTF was 64%, 70%, and 82% with OS rates of 75%, 80%, and 86% for patients treated with standard COPP/ABVD, BEACOPP baseline, and BEACOPP escalated, respectively (P < 0.001) [62]. The higher overall chemotherapy doses, as given in the escalated BEACOPP scheme, appear to provide greater disease control than any of the previous or contemporary regimens. This is supported by the very low number of deaths due to the progression of lymphoma (2.8%). The GHSG has conducted a series of studies, HD12, HD15, and HD18, all using escalated BEACOPP in advanced HL patients (under the age of 61) whose results replicate closely those of the escalated BEACOPP arm in the HD9 study [74–76]. The GHSG reported early on its concerns for the immediate toxicity, especially among patients older than 65, and, in younger patients, impaired fertility and risk of MDS or secondary AML. A review of the HD9 results concerning the cumulative incidence of all second tumors at 10 years confirmed that the rate for AML/MDS was lower after COPP/ABVD (0.4%) versus BEACOPP baseline (2.2%) and BEACOPP escalated (3.2%; log-rank test; P = 0.03). However, counting all secondary malignancies, there was no difference (5.3% after COPP/ ABVD, 7.9% after BEACOPP baseline, and 6.5% after BEACOPP escalated) [62]. The immediate and long-term toxic effects of escalated BEACOPP and the reluctance of many specialists to consider COPP/ABVD as a standard 10 Principles of Chemotherapy in Hodgkin Lymphoma 209 comparator have hindered acceptance of escalated BEACOPP as a new standard of care. Two Italian trials, HD2000 and GSM-HD, have demonstrated superior PFS with escalated BEACOPP in comparison to ABVD. In HD2000, BEACOPP resulted in an 81% (95% CI, 70–89%) 5-year PFS versus 68% (95% CI, 56–78%) for ABVD, but no significant OS difference was observed [77]. Similarly, the GSM-HD trial demonstrated a higher 3-year FFP for escalated plus baseline BEACOPP (4 + 4) versus ABVD (87 ± 3% and 71 ± 4%), respectively, but freedom from second progression (FF2P) and OS were alike [78]. ABVD was declared preferable, taking into account the lesser toxicity, including fewer toxic deaths (one vs. six). The outstanding results of escalated BEACOPP, despite the toxicity, have made it most appealing for high-risk patients. This has been called into question by results in two recent randomized clinical trials. In a multi-institutional Italian trial comparing ABVD with BEACOPP (4 cycles escalated dose + 4 cycles standard dose) for patients with stages IIB, III, or IV HL, the superior freedom from first progression for BEACOPP was confirmed (at 7 years, 73% for ABVD vs. 85% for BEACOPP; P = 0.004), which was the primary endpoint of the trial. However, there was no significant difference in freedom from second relapse following ASCT or in OS between the two treatment arms. The treatment- related mortality was 4% for BEACOPP vs. 1% for ABVD [79]. This suggests that most patients can be treated initially with ABVD and only those who relapse be salvaged with ASCT and thus exposed to a treatment- related mortality similar to that with initial BEACOPP treatment. The EORTC randomized patients with high-risk stages III or IV HL (international prognostic score ≥ 3) to BEACOPP (4 cycles dose escalated + 4 cycles standard dose) or ABVD. There was no significant difference in 4-year event-free survival (EFS) or OS, which was the primary endpoint, although this trial also confirmed a superior PFS for BEACOPP [80]. Progression-free survival may not be the most clinically important treatment result, and these two trials suggest that ABVD is an acceptable initial treatment approach even for high-risk advanced-stage HL patients because of the effectiveness of salvage ASCT in the minority of patients who relapse. As with ABVD, it was found that omission of bleomycin because of toxicity during treatment with BEACOPP did not have an adverse impact on PFS or OS. In addition, with this intensive regimen, omission of vincristine during treatment because of toxicity also had no adverse impact on these outcomes [81]. 10.2.2.6 High-Dose Treatment and Autologous Stem Cell Transplantation as Part of Initial Therapy Attempts have been made to improve results by using intensified consolidation and peripheral blood stem cell (PBSC) rescue for patients considered at high risk. Three randomized studies have explored this concept for HL. The Scotland and Newcastle Lymphoma Group HD3 study randomized 65 out of 126 high-risk patients, resulting in a nonsignificant advantage for the conventional arm (time to treatment failure 85% vs. 79%; P = 0.35) [82]. A European study of similar design randomized 163 high-risk patients achieving CR or partial response (PR) after four cycles of ABVD or an equivalent regimen to receive high-dose therapy plus ASCT (83 patients) or four more cycles of conventional chemotherapy (80 patients). There was no evidence of a benefit to the group receiving high-dose therapy (CR 92% vs. 89%, 5-year FFS 75% vs. 82%, and OS 88% vs. 88%, respectively) [83]. The Groupe Ouest-Est d’Etude des Leucémies et Autres Maladies du Sang (GOELAMS) undertook a randomized study in 158 high-risk patients, comparing conventional intensive chemotherapy with vindesine (5 mg/m2), doxorubicin (99 mg/ m2), carmustine (140 mg/m2), etoposide (600 mg/ m2), and methylprednisolone (600 mg/m2) (VABEM) followed by low-dose lymph node irradiation in 82 patients versus four cycles of ABVD followed by myeloablative carmustine (300 mg/m2), etoposide (800 mg/m2), cytarabine (1600 mg/m2), and melphalan (140 mg/m2) and ASCT in 76 patients. The results were remarkably D. Straus and M. Hertzberg 210 similar for CR (89% vs. 88%), 5-year FFTF (79% vs. 75%), and OS (87% vs. 86%) [84]. In summary, there is no evidence to support the use of high-dose consolidation at first remission in HL at present. when compared with addition of IFRT; OS did not differ between groups, as the 22 patients who relapsed without further IFRT were successfully treated with salvage therapy. Of note, 5 of the 22 received only radiation therapy as a salvage treatment, and only 7 of 22 received chemotherapy 10.2.2.7 Risk-Adapted Regimens followed by ASCT. Negative PET was defined as Based on PET a Deauville score of 1–2 (FDG uptake less than Response to treatment for classical HL (cHL) is mediastinal blood pool). assessed by positron emission tomography– Another phase 2 trial confirmed an excellent computed tomography (PET/CT) at end of treat- PFS for most patients treated with a short ment (EOT). Negative PET/CT is associated course of ABVD alone. CALGB 50604 treated with a 10% or lower likelihood of relapse [85]. patients with stages I/II non-bulky cHL with Interim PET/CT after one or two cycles of two cycles of ABVD. Interim PET/CT was perABVD or similar regimens is also highly predic- formed and centrally reviewed. Patients whose tive of outcome [86, 87]. interim PET/CT was negative, defined as Three recent clinical trials have utilized PET/ Deauville scores of 1–3 (FDG uptake less than CT to determine if negative PET after or during liver), received two more cycles of ABVD (total treatment will identify a population of early- four cycles) and no irradiation (135/149; 91%). stage patients with non-bulky disease who can Patients whose interim PET/CT was positive safely be treated with ABVD alone (Table 10.4). received two cycles of more intensive chemoThe Randomized Phase 3 Trial to Determine the therapy with escalated BEACOPP and IFRT to Role of FDG-PET Imaging in Clinical Stages IA/ a dose of 3060 cGy (13/149; 9%). Estimated IIA Hodgkin lymphoma (RAPID) found high PFS was 91% at 3 years for the interim PETrates of 3-year PFS among patients who were negative group. The estimated 3-year PFS for PET-negative after three cycles of ABVD, regard- the interim PET-positive group was signifiless of whether they received IFRT or no further cantly lower, at 66%, than for the interim PETtreatment (90.8% vs. 94.6%; P = 0.16) [88]. negative group (P = 0.011), s uggesting that the Though the PFS rate for chemotherapy alone was intensive treatment regimen did not provide excellent, non-inferiority criteria were not met benefit [89]. Table 10.4 Salvage regimens in common use for recurrent/refractory Hodgkin lymphoma drugs Dexa-BEAM Dexamethasone Carmustine Etoposide Cytarabine Melphalan DHAP Dexamethasone Cytarabine Cisplatin ESHAP Etoposide Cytarabine Cisplatin Methylprednisolone Dose, mg/m2 Route 24 mg daily 60 250 100 bd 20 Po Iv Iv Iv Iv 40 mg daily 2000 bd 100 Iv Iv Ivi 40 2000 25 500 mg daily Iv Iv Ivi Iv Schedule q. 21d d1–10 d2 d4–7 d4–7 d3 q. 21d d1–4 d2 d1 q. 21d d1–4 d5 d1–4 d1–5 10 Principles of Chemotherapy in Hodgkin Lymphoma 211 Table 10.4 (continued) ICE Ifosfamide Carboplatin Etoposide GDP Gemcitabine Dexamethasone Cisplatin GVD Gemcitabine Vinorelbine Liposomal doxorubicin IGEV Ifosfamide Gemcitabine Vinorelbine Prednisone BeGEV Bendamustine Gemcitabine Vinorelbine Prednisone BV-Benda Bendamustine Brentuximab vedotin BV-ESHAP Brentuximab vedotin Etoposide Cytarabine Cisplatin Methylprednisolone BV-DHAP Brentuximab vedotin Dexamethasone Cytarabine Cisplatin Dose, mg/m2 Route 5000 AUC 5 100 Ivi Iv Iv 1000 40 mg daily 75 Iv Po Iv Schedule q. 21d d2 d2 d1–3 q. 21d d1 and 8 d1–4 d1 1000 20 15 Iv Iv Iv d1 and 8 d1 and 8 d1 and 8 2000 800 20 100 Iv Iv Iv Po d1–4 d1 and 4 d1 and 4 d1–4 90 800 20 100 Iv Iv Iv Po d2 and 3 d1 and 4 d1 d1–4 90 1.8 mg/kg Iv Iv d1 and 2 d1 0.9–1.2–1.8 mg/kg 40 2000 25 500 mg daily Iv Iv Iv Iv Iv d1–4 d5 d1–4 d1–5 1.8 mg/kg 40 mg daily 2000 bd 100 Iv Iv Iv Iv d1 d1–4 d2 d1 The larger phase 3 H10 trial compared a similar interim PET-adapted approach to combined- modality therapy (CMT) for all patients [90]. Patients with early-stage cHL received two cycles of ABVD and underwent interim PET/ CT. Interim PET-negative favorable patients in the PET-adapted arm received two more cycles of ABVD (total four) and no RT, while those in the CMT arm received one more cycle of ABVD (total three) and involved-node radiation therapy (INRT). Favorable patients who were interim PET-positive in the PET-adapted arm received two cycles of escalated BEACOPP and INRT, while those in the CMT arm received two more cycles of ABVD and INRT. Interim PET-negative unfavorable patients in the PET-adapted arm received four more cycles of ABVD (total six) and no RT, while those who were interim PETnegative in the CMT arm received two more cycles of ABVD (total four) and INRT. Interim PET-positive unfavorable patients in the PET- adapted arm received two cycles of escalated BEACOPP and INRT, while interim PET-positive patients in the CMT arm received two more 212 cycles of ABVD (total four) and INRT. Overall, in favorable and unfavorable groups together, this trial demonstrated a 5-year PFS benefit for a CMT regimen as compared with a PET-adapted regimen (91% vs. 77%; P = 0.002) [91]. The 5-year PFS for interim PET-negative patients in the favorable group was 87% for the PET-adapted arm versus 99% for the CMT arm. The 5-year PFS for interim PET-negative unfavorable patients was 90% for the PET-adapted arm versus 92% for the CMT arm. PFS favored CMT over PET-adapted treatment, and non-inferiority could not be demonstrated in the large number patients undergoing analysis. In the recent HD16 randomized trial, early- stage favorable cHL patients received two cycles of ABVD + 20 Gy IFRT (control) or two cycles of ABVD plus PET, with PET-negative patients receiving no further treatment and PET-positive patients receiving 20 Gy IFRT (risk adapted). Following two cycles of ABVD only, PET- negative patients had a relapse rate of 10% at 5 year PFS, higher than those who received standard two cycle ABVD + 20 Gy IFRT [92]. These trials demonstrate a 5–10% higher relapse rate for 2–4 cycles of ABVD alone as compared with CMT for favorable early-stage cHL. Opinions differ as to whether it is more important to reduce the late risks of radiotherapy with chemotherapy only, given the excellent salvage options, or to provide a more optimal PFS with frontline treatment by adding radiotherapy to chemotherapy. Four recent trials have employed interim PET after two cycles of chemotherapy to tailor treatment for patients with advanced-stage cHL. S0816, a phase 2 trial conducted by the US Intergroup, treated stage III and IV patients with two cycles of ABVD followed by interim PET/ CT. Interim PET-negative patients received 4 more cycles of ABVD, while those who were interim PET-positive received two cycles of escalated BEACOPP. The estimated 2-year PFS was 82% for interim PET-negative patients and 64% for interim PET-positive patients. Of note, there were two treatment-related deaths (4%) among D. Straus and M. Hertzberg the 49 interim PET-positive patients who receive escalated BEACOPP [93]. The Response-Adapted Trial in Advanced Hodgkin Lymphoma (RATHL) treated patients with stages IIB, III, and IV and high-risk stage IIA with two cycles of ABVD followed by interim PET/CT. Patients who were interim PET-negative were randomized to treatment with four cycles of ABVD or four cycles of AVD without bleomycin. Patients who were interim PET-positive were treated with escalated BEACOPP or BEACOPP-14 depending on results of further interim PET/CT studies. For post-cycle 2 interim PET-negative patients, the 3-year PFS was 85.7% for the ABVD and 84.4% for the ABVD/AVD groups, respectively. For the interim PET-positive patients treated with BEACOPP, the 3-year PFS was 67.5%. These findings justify reducing exposure to bleomycin with its attendant pulmonary toxicity for patients with advanced-stage cHL who are interim PETnegative after two cycles of ABVD [52]. The HD18 trial administered two cycles of escalated BEACOPP to patients with advanced-stage cHL followed by interim PET. Patients who were interim PET-negative just received two more cycles of escalated BEACOPP and no additional radiotherapy. PET-positive patients after two cycles of escalated BEACOPP received a total of four or six additional cycles and radiotherapy to PET-positive residual disease. For PET-negative patients, 5-year PFS was 91.2% for 8/6 escalated BEACOPP and 91.8% for four escalated BEACOPP, and there was less toxicity in the latter group [94]. The LYSA AHL2011 trial randomized advanced-stage cHL patients to standard treatment with six cycles of escalated BEACOPP plus interim PET after two and four cycles or experimental treatment. In the experimental arm, treatment was initiated with two cycles of escalated BEACOPP. Following interim PET/CT, treatment was changed to four cycles of ABVD in interim PET-negative patients, while interim PET-positive patients continued four cycles of escalated BEACOPP. There was no significant difference in 4-year PFS between the standard (86.2%) and 10 Principles of Chemotherapy in Hodgkin Lymphoma 213 experimental arms (85.7%). These results suggest that treatment can be safely de-escalated to ABVD for patients with advanced-stage disease who are PET-negative after two cycles of escalated BEACOPP (Casanovas O, Presentation USHL11, Cologne, October 29, 2018). The goal of a PET-adapted approach, by starting with either BEACOPP escalated or ABVD, is to maintain efficacy and minimize long-term toxicities. Ideally, a more effective risk-allocation strategy would use novel biomarkers such as TARC or ctDNA, with or without baseline PET parameters such as total metabolic tumor volume (TMTV). Such a strategy would allow patients with highestrisk baseline features to receive the potential benefit of more-intensive initial therapy and would identify those for whom less-intensive or de- escalation strategies can be successfully applied. ment for all patients with stages III and IV cHL or in particular subgroups [95]. 10.2.2.8 Incorporation of Antibody- Drug Conjugate in Primary Treatment of AdvancedStage cHL Brentuximab vedotin (BV) is an anti-CD30drug conjugate consisting a monoclonal antibody to CD30 linked to monomethyl auristatin E, a tubulin inhibitor. As a single agent in relapsed/refractory cHL, it achieves an overall response rate of 75% and a CR rate of 34%, which is at least twice as effective as any single conventional chemotherapy agent [16]. The ECHELON-1 trial was an open-label, multicenter randomized phase 3 trial of six cycles of standard ABVD versus six cycles of BV + AVD in newly diagnosed patients with stages III and IV cHL. The 2-year modified PFS was 77.2% for ABVD and 82.1% for BV + AVD (P = 0.03). This result led to approval of BV + AVD for this indication by the US Food and Drug Administration. Some subgroups seemed to particularly benefit from BV + AVD, and further analyses are being performed to better define these groups. Given cost and toxicity considerations, it is unclear, at least in the USA, whether BV + AVD will be adopted as a standard treat- 10.3 Chemotherapy Treatment for Recurrent and Refractory Hodgkin Lymphoma 10.3.1 New Systemic Treatments There have been relatively few new conventional cytotoxic agents developed recently for HL, but both monoclonal antibodies, immune therapies, and small molecule therapeutics targeting specific abnormal pathways in HL have shown some promising results. Antibody therapies have been directed at relatively specific molecules, such as CD30 on the surface of Reed-Sternberg cells, but the results with an unconjugated anti-CD30 were discouraging, probably because it targets only a small proportion of the cells within a mass of lymphoma [96]. On the other hand, antibody-drug conjugates (ADC) have shown very promising results, with a response rate of 75% reported using brentuximab vedotin for patients with recurrent and refractory disease, as described in Sect. 10.2.1 [16]. Anti-CD20, given with the intention of targeting the infiltrating B cells and interrupting autocrine growth factor loops, has shown some promise in an early pilot study [97], but awaits confirmatory data from a prospective trial. This approach may find more application in the treatment of nodular lymphocyte predominant disease, in which CD20 is present on the surface of the malignant cells [98]. Among the small molecule therapies being tested, proteosome inhibitors have been disappointing in HL [99], whereas inhibitors of histone deacetylase (HDACi) have resulted in significant responses in early-phase studies, despite significant marrow toxicity [100]. It is not clear whether the principal target of HDACis is the malignant cell itself or the surrounding inflammatory infiltrate, but further studies using D. Straus and M. Hertzberg 214 a range of more- or less-specific agents targeting different members of the HDAC family may yield further information. 5. 6. 10.4 Conclusions A variety of pharmacologic hypotheses have been tested in the course of the last 50 years, and none has been found entirely satisfactory for predicting the outcomes of treatment. The superiority of ABVD over MOPP is established. Similarly, the more effective multiagent BEACOPP regimen is being used in more and more countries and groups. There appears to be a potential trade-off between the intensity of chemotherapy and the value of consolidation radiotherapy in advanced disease: it is not clear whether any chemotherapy is intensive enough for radiation to be dropped altogether, but functional imaging holds promise for lowering the proportion of patients irradiated very significantly. As treatment has evolved, the balance between toxicity and efficacy has been established, and new approaches using response-adapted therapy hold the promise of identifying the minority of patients for whom early intensification is a necessity, while allowing de-escalation of treatment in those destined to do well. The addition of brentuximab vedotin, the antibody-drug conjugate, has slightly improved efficacy in the treatment of stages III and IV HL. Finally, there are a small number of novel agents currently undergoing testing against recurrent and refractory disease which appear to hold some promise. References 1. Wilkinson JF, Fletcher F (1947) Effect of beta- chloroethylamine hydrochlorides in leukaemia, Hodgkin’s disease, and polycythaemia vera; report on 18 cases. Lancet 2(6476):540–545 2. Papac RJ (2001) Origins of cancer therapy. Yale J Biol Med 74(6):391–398 3. Zubrod CG (1979) Historic milestones in curative chemotherapy. Semin Oncol 6:490–505 4. Gross R, Lambers K (1958) Erste erfarhungen in der Behandlung malignen tumoren mit einem 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. neuen N-lost phosphamidester. Dtsch Med Wschr 83:458–462 Rotolo V (1968) Vincaleukoblastine in the therapy of malignant neoplasms. Friuli Med 23(1):31–52 Mathe G, Cattan A, Amiel JL, Schwarzenberg L, Schneider M (1969) Experimental therapeutic trials of leukemia and hematosarcomas: technologic and philosophic aspects. Ann N Y Acad Sci 164(3):776–792 Burchenal JH (1975) From wild fowl to stalking horses: alchemy in chemotherapy. Cancer 35:1121–1135 Gilman A (1963) The initial clinical trial of nitrogen mustard. Am J Surg 105(574):578 Wagener DJT (2009) The history of oncology. Springer, Berlin Mathe G, Schweisguth O, Schneider M, Amiel JL, Cattan A, Schwarzenberg L et al (1964) Value of vincaleukoblastine in the treatment of Hodgkin’s disease and other hematosarcomas and leukemias. Sem Ther 40(5):320–324 Tubiana M, Henry-Amar M, Hayat M, Breur K, Werf-Messing B, Burgers M (1979) Long-term results of the E.O.R.T.C. randomized study of irradiation and vinblastine in clinical stages I and II of Hodgkin’s disease. Eur J Cancer 15(5):645–657 Rosenberg SA, Kaplan HS (1966) Evidence for an orderly progression in the spread of Hodgkin’s disease. Cancer Res 26(6):1225–1231 Tubiana M, Hayat M, Henry-Amar M, Breur K, van der Werf MB, Burgers M (1981) Five-year results of the E.O.R.T.C. randomized study of splenectomy and spleen irradiation in clinical stages I and II of Hodgkin’s disease. Eur J Cancer 17(3): 355–363 Bergsagel DE, Alison RE, Bean HA, Brown TC, Bush RS, Clark RM et al (1982) Results of treating Hodgkin’s disease without a policy of laparotomy staging. Cancer Treat Rep 66:717–731 Selby P, McElwain TJ, Canellos G (1987) Chemotherapy for Hodgkin’s disease. Section I: MOPP and its variants. In: Selby P, McElwain TJ (eds) Hodgkin’s disease. Blackwell, Oxford Younes A, Gopal AK, Smith SE, Ansell SM, Rosenblatt JD, Savage KJ et al (2012) Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol 30(18):2183–2189 Johnson PW, Federico M, Fossa A, Barrington SF, Kirkwood A, Roberts TH et al (2013) Response rates and toxicity of response-adapted therapy in advanced Hodgkin lymphoma: initial results. From The International RATHL Study. Hematologica 98(s2):2 Bernard J (1966) Current general principles of the treatment of Hodgkin’s disease, lymphosarcoma and reticulosarcoma. Rev Prat 16(7):871–879 Lacher MJ, Durant JR (1965) Combined vinblastine and CHLORAMBUCIL therapy of HODGKIN’s disease. Ann Intern Med 62:468–476 10 Principles of Chemotherapy in Hodgkin Lymphoma 20. DeVita VT Jr, Carbone PP (1967) Treatment of Hodgkin’s disease. Med Ann 36(4):232–234 21. DeVita VT, Serpick AA, Carbone PP (1970) Combination chemotherapy in the treatment of advanced Hodgkin’s disease. Ann Intern Med 73(6):881–895 22. DeVita VT, Simon RM, Hubbard SM, Young RC, Berard CW, Moxley JH et al (1980) Curability of advanced Hodgkin’s disease with chemotherapy. Ann Intern Med 92(5):587–595 23. Longo DL, Young RC, Wesley M, Hubbard SM, Duffey PL, Jaffe ES et al (1986) Twenty years of MOPP therapy for Hodgkin’s disease. J Clin Oncol 4(9):1295–1306 24. Canellos GP, Anderson JR, Propert KJ, Nissen N, Cooper MR, Henderson ES et al (1992) Chemotherapy of advanced Hodgkin’s disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med 327(21):1478–1484 25. Carde P, MacKintosh FR, Rosenberg SA (1983) A dose and time response analysis of the treatment of Hodgkin’s disease with MOPP chemotherapy. J Clin Oncol 1(2):146–153 26. Frei E III, Luce JK, Gamble JF, Coltman CA Jr, Constanzi JJ, Talley RW et al (1973) Combination chemotherapy in advanced Hodgkin’s disease: induction and maintenance of remission. Ann Intern Med 79(3):376–382 27. Somers R, Carde P, Henry-Amar M, Tarayre M, Thomas J, Hagenbeek A et al (1994) A randomized study in stage IIIB and IV Hodgkin’s disease comparing eight courses of MOPP versus an alteration of MOPP with ABVD: a European Organization for Research and Treatment of Cancer lymphoma cooperative group and Groupe Pierre-et-Marie-curie controlled clinical trial. J Clin Oncol 12(2):279–287 28. Carde P, Hayat M, Cosset JM, Somers R, Burgers JM, Sizoo W et al (1988) Comparison of total nodal irradiation versus combined sequence of mantle irradiation with mechlorethamine, vincristine, procarbazine, and prednisone in clinical stages I and II Hodgkin’s disease: experience of the European Organization for Research and Treatment of Cancer. NCI Monogr 6:303–310 29. Young RC, Chabner BA, Canellos GP, Schein PS, DeVita VT (1973) Maintenance chemotherapy for advanced Hodgkin’s disease in remission. Lancet 301(7816):1339–1343 30. Lowenbraun STAN, DeVita VT, Serpick AA (1970) Combination chemotherapy with nitrogen mustard, vincristine, Procarbazine and prednisone in previously treated patients with Hodgkin’s disease. Blood 36(6):704–717 31. Fisher RI, DeVita VT, Hubbard SP, Simon R, Young RC (1979) Prolonged disease-free survival in Hodgkin’s disease with MOPP reinduction after first relapse. Ann Intern Med 90(5):761–763 32. Arseneau JC, Sponzo RW, Levin DL, Schnipper LE, Bonner H, Young RC et al (1972) Non lymphomatous malignant tumors complicating Hodgkin’s dis- 215 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. ease : possible association with intensive therapy. N Engl J Med 287(22):1119–1122 Weiden PL, Lerner KG, Gerdes A, Heywood JD, Fefer A, Thomas ED (1973) Pancytopenia and leukemia in Hodgkin’s disease: report of three cases. Blood 42(4):571–577 Sherins RJ, DeVita VT Jr (1973) Effect of drug treatment for lymphoma on male reproductive capacity. Studies of men in remission after therapy. Ann Intern Med 79(2):216–220 Corder MP, Young RC, Brown RS, Devita VT (1972) Phytohemagglutinin-induced lymphocyte transformation: the relationship to prognosis of Hodgkin’s disease. Blood 39(5):595–601 Crowther D, Wagstaff J, Deakin D, Todd I, Wilkinson P, Anderson H et al (1984) A randomized study comparing chemotherapy alone with chemotherapy followed by radiotherapy in patients with pathologically staged IIIA Hodgkin’s disease. J Clin Oncol 2(8):892–897 Nicholson WM, Beard ME, Crowther D, Stansfeld AG, Vartan CP, Malpas JS et al (1970) Combination chemotherapy in generalized Hodgkin’s disease. Br Med J 3(713):7–10 Ranson MR, Radford JA, Swindell R, Dikin DP, Wilkinson PM, Harris M et al (1991) An analysis of prognostic factors in stage III and IV Hodgkin’s disease treated at a single centre with MVPP. Ann Oncol 2(6):83–89 Dady PJ, McElwain TJ, Austin DE, Barrett A, Peckham MJ (1982) Five years' experience with ChlVPP: effective low-toxicity combination chemotherapy for hodgkin’s diseasechlvpp advanced HL. Br J Cancer 45:851–859 McElwain TJ, Toy J, Smith E, Peckham MJ, Austin DE (1977) A combination of chlorambucil, vinblastine, procarbazine and prednisolone for treatment of Hodgkin’s disease. Br J Cancer 36(276):280 Luce JK, Gamble JF, Wilson HE, Monto RW, Isaacs BL, Palmer RL et al (1971) Combined cyclophosphamide vincristine, and prednisone therapy of malignant lymphoma. Cancer 28(2):306–317 Bonadonna G, Monfardini S (1969) Cardiac toxicity of daunorubicin. Lancet 1(7599):837 Bonadonna G, Monfardini S, Oldini C (1969) Comparative effects of vinblastine and procarbazine in advanced Hodgkin’s disease. Eur J Cancer (1965) 5(4):393–402 Frei E, Luce JK, Talley RW, Veitkvicius VK, Wilson HE (1972) 5-(3,3-dimethyl-1-triazeno)imidazole-4- carboxamide (NSC-45388) in the treatment of lymphoma. Cancer Treat Rep 56(5):667–670 O'Bryan RM, Luce JK, Tailey RW, Gottlieb JA, Baker LH, Bonadonna G (1973) Phase II evaluation of adriamycin in human neoplasia. Cancer 32(1):1–8 Bonadonna G, Zucali R, Monfardini S, De Lena M, Uslenghi C (1975) Combination chemotherapy of Hodgkin’s disease with adriamycin, bleomycin, vinblastine, and imidazole carboxamide versus MOPP. Cancer 36(1):252–259 D. Straus and M. Hertzberg 216 47. Duggan DB, Petroni GR, Johnson JL, Glick JH, Fisher RI, Connors JM et al (2003) Randomized comparison of ABVD and MOPP/ABV hybrid for the treatment of advanced Hodgkin’s disease: report of an intergroup trial. J Clin Oncol 21(4):607–614 48. Boleti E, Mead GM (2007) ABVD for Hodgkin’s lymphoma: full-dose chemotherapy without dose reductions or growth factors. Ann Oncol 18(2):376–380 49. Martin WG, Ristow KM, Habermann TM, Colgan JP, Witzig TE, Ansell SM (2005) Bleomycin pulmonary toxicity has a negative impact on the outcome of patients with Hodgkin’s lymphoma. J Clin Oncol 23(30):7614–7620 50. Straus DJ, Portlock CS, Qin J, Myers J, Zelenetz AD, Moskowitz C et al (2004) Results of a prospective randomized clinical trial of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by radiation therapy (RT) versus ABVD alone for stages I, II, and IIIA nonbulky Hodgkin disease. Blood 104(12):3483–3489 51. Canellos GP, Duggan D, Johnson J, Niedzwiecki D (2004) How important is bleomycin in the adriamycin + bleomycin + vinblastine + dacarbazine regimen? J Clin Oncol 22(8):1532–1533 52. Johnson P Adapted treatment guided by interim PET-CT scan in advanced Hodgkin’s lymphoma. N Engl J Med 374(25):2419–2429 53. Norton L, Simon R (1977) Tumor size, sensitivity to therapy, and design of treatment schedules. Cancer Treat Rep 61:1307–1317 54. Diehl V, Franklin J, Pfreundschuh M, Lathan B, Paulus U, Hasenclever D et al (2003) Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin’s disease. N Engl J Med 348(24):2386–2395 55. Linch DC, Winfield D, Goldstone AH, Moir D, Hancock B, McMillan A et al (1993) Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin’s disease: results of a BNLI randomised trial. Lancet 341(8852):1051–1054 56. Schmitz N, Pfistner B, Sextro M, Sieber M, Carella AM, Haenel M et al (2002) Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin’s disease: a randomised trial. Lancet 359(9323):2065–2071 57. Hasenclever D, Brosteanu O, Gerike T, Loeffler M (2001) Modelling of chemotherapy: the effective dose approach. Ann Hematol 80(Suppl 3):B89–B94 58. Hasenclever D, Loeffler M, Diehl V (1996) Rationale for dose escalation of first line conventional chemotherapy in advanced Hodgkin’s disease. German Hodgkin’s Lymphoma Study Group. Ann Oncol 7(Suppl 4):95–98 59. Owadally WS, Sydes MR, Radford JA, Hancock BW, Cullen MH, Stenning SP et al (2010) Initial dose intensity has limited impact on the out- 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. come of ABVD chemotherapy for advanced Hodgkin lymphoma (HL): data from UKLG LY09 (ISRCTN97144519). Ann Oncol 21:568–573 Brosteanu O, Hasenclever D, Loeffler M, Diehl V, Group GH (2004) Low acute hematological toxicity during chemotherapy predicts reduced disease control in advanced Hodgkin’s disease. Ann Hematol 83(3):176–182 Ribrag V, Koscielny S, Casasnovas O, Cazeneuve C, Brice P, Morschhauser F et al (2009) Pharmacogenetic study in Hodgkin lymphomas reveals the impact of UGT1A1 polymorphisms on patient prognosis. Blood 113(14):3307–3313 Engert A, Diehl V, Franklin J, Lohri A, Dorken B, Ludwig WD et al (2009) Escalated-dose BEACOPP in the treatment of patients with advanced-stage Hodgkin’s lymphoma: 10 years of follow-up of the GHSG HD9 study. J Clin Oncol 27(27): 4548–4554 Henry-Amar M, Hayat M, Meerwaldt JH, Burgers M, Carde P, Somers R et al (1990) Causes of death after therapy for early stage Hodgkin’s disease entered on EORTC protocols. EORTC lymphoma cooperative group. Int J Radiat Oncol Biol Phys 19(5):1155–1157 Van Leeuwen FE, Klokman WJ, Hagenbeek A, Noyon R, Van den Beltdusebout AW, Van Kerkhoff EHM et al (1994) 2nd cancer risk following hodgkins-disease - a 20-year follow-up-study. J Clin Oncol 12(2):312–325 Bartlett NL, Rosenberg SA, Hoppe RT, Hancock SL, Horning SJ (1995) Brief chemotherapy, Stanford V, and adjuvant radiotherapy for bulky or advanced- stage Hodgkin’s disease: a preliminary report. J Clin Oncol 13(5):1080–1088 Horning SJ, Williams J, Bartlett NL, Bennett JM, Hoppe RT, Neuberg D et al (2000) Assessment of the Stanford V regimen and consolidative radiotherapy for bulky and advanced Hodgkinís disease: eastern cooperative oncology group pilot study E1492. J Clin Oncol 18(5):972 Horning SJ, Hoppe RT, Breslin S, Bartlett NL, Brown BW, Rosenberg SA (2002) Stanford V and radiotherapy for locally extensive and advanced Hodgkin’s disease: mature results of a prospective clinical trial. J Clin Oncol 20(3):630–637 Gobbi PG, Levis A, Chisesi T, Broglia C, Vitolo U, Stelitano C et al (2005) ABVD versus modified Stanford V versus MOPPEBVCAD with optional and limited radiotherapy in intermediate- and advanced-stage Hodgkin’s lymphoma: final results of a multicenter randomized trial by the Intergruppo Italiano Linfomi. J Clin Oncol 23(36):9198–9207 Hoskin PJ, Lowry L, Horwich A, Jack A, Mead B, Hancock BW et al (2009) Randomized comparison of the Stanford V regimen and ABVD in the treatment of advanced Hodgkin’s lymphoma: United Kingdom National Cancer Research Institute lymphoma group study ISRCTN 64141244. J Clin Oncol 27(32):5390–5396 10 Principles of Chemotherapy in Hodgkin Lymphoma 70. Gordon LI, Hong F, Fisher RI, Bartlett NL, Connors JM, Gascoyne RD et al (2013) Randomized phase III trial of ABVD versus Stanford V with or without radiation therapy in locally extensive and advanced- stage Hodgkin lymphoma: an intergroup study coordinated by the eastern cooperative oncology group (E2496). J Clin Oncol 31(6):684–691 71. Radford JA, Rohatiner AZS, Ryder WDJ, Deakin DP, Barbui T, Lucie NP et al (2002) ChlVPP/EVA hybrid versus the weekly VAPEC-B regimen for previously untreated Hodgkin’s disease. J Clin Oncol 20(13):2988–2994 72. Green JA, Dawson AA, Fell LF, Murray S (1980) Measurement of drug dosage intensity in MVPP therapy in Hodgkin’s disease. Br J Clin Pharmacol 9:511–514 73. Diehl V, Sieber M, Ruffer U, Lathan B, Hasenclever D, Pfreundschuh M et al (1997) BEACOPP: an intensified chemotherapy regimen in advanced Hodgkin’s disease. The German Hodgkin’s lymphoma study group. Ann Oncol 8(2):143–148 74. Diehl V, Haverkamp H, Mueller R, Mueller- Hermelink H, Cerny T, Markova J et al (2009) Eight cycles of BEACOPP escalated compared with 4 cycles of BEACOPP escalated followed by 4 cycles of BEACOPP baseline with or without radiotherapy in patients in advanced stage Hodgkin lymphoma (HL): final analysis of the HD12 trial of the German Hodgkin study group (GHSG). ASCO Meet Abst 27(15S):8544 75. Engert A, Franklin J, Mueller RP, Eich HT, Gossmann A, Mueller-Hermelink HK et al (2006) HD12 randomised trial comparing 8 dose-escalated cycles of BEACOPP with 4 escalated and 4 baseline cycles in patients with advanced stage Hodgkin lymphoma (HL): an analysis of the German Hodgkin lymphoma study group (GHSG), University of Cologne, Cologne, Germany. ASH Annu Meet Abstr 108(11):99 76. Kobe C, Dietlein M, Franklin J, Markova J, Lohri A, Amthauer H et al (2008) Positron emission tomography has a high negative predictive value for progression or early relapse for patients with residual disease after first-line chemotherapy in advanced-stage Hodgkin lymphoma. Blood 112(10):3989–3994 77. Federico M, Luminari S, Iannitto E, Polimeno G, Marcheselli L, Montanini A et al (2009) ABVD compared with BEACOPP compared with CEC for the initial treatment of patients with advanced Hodgkin’s lymphoma: results from the HD2000 Gruppo Italiano per lo studio Dei Linfomi trial. J Clin Oncol 27(5):805–811 78. Gianni AM, Rambaldi A, Zinzani P, Levis A, Brusamolino E, Pulsoni A et al (2008) Comparable 3-year outcome following ABVD or BEACOPP first-line chemotherapy, plus pre-planned high-dose salvage, in advanced Hodgkin lymphoma (HL): a randomized trial of the Michelangelo, GITIL and IIL cooperative groups. ASCO Meet Abstr 26(15 Suppl):8506 217 79. Viviani S, Zinzani PL, Rambaldi A, Brusamolino E, Levis A, Bonfante V et al (2011) ABVD versus BEACOPP for Hodgkin’s lymphoma when high-dose salvage is planned. N Engl J Med 365(3):203–212 80. Carde P, Karrasch M, Fortpied C, Brice P, Khaled HM, Caillot D et al (2012) ABVD (8cycles) versus BEACOPP (4 escalated cycles => 4 baseline) in stage III-IV high-risk Hodgkin Lymphoma (HL): First results of EORTC 20012 Intergroup randomized phase III clinical trial. J Clin Oncol 30:abstr 8002 81. von Tresckow B, Haverkamp H, Boll B, Eichenauer DA, Sasse S, Fuchs M et al (2013) Impact of dose reduction of bleomycin and vincristine in patients with advanced Hodgkin lymphoma treated with BEACOPP: A comprehensive analysis of the German Hodgkin Study Group (GHSG) HD12 and HD15 trials. Blood 122(21):Abstract 637 82. Proctor SJ, Mackie M, Dawson A, Prescott B, Lucraft HL, Angus B et al (2002) A population- based study of intensive multi-agent chemotherapy with or without autotransplant for the highest risk Hodgkin’s disease patients identified by the Scotland and Newcastle lymphoma group (SNLG) prognostic index: a Scotland and Newcastle lymphoma group study (SNLG HD III). Eur J Cancer 38(6):795–806 83. Federico M, Bellei M, Brice P, Brugiatelli M, Nagler A, Gisselbrecht C et al (2003) High-dose therapy and autologous stem-cell transplantation versus conventional therapy for patients with advanced Hodgkin’s lymphoma responding to front-line therapy. J Clin Oncol 21(12):2320–2325 84. Arakelyan N, Berthou C, Desablens B, De Guibert S, Delwail V, Moles MP et al (2008) Radiation therapy versus 4 cycles of combined doxorubicin, bleomycin, vinblastine, and Dacarbazine plus Myeloablative chemotherapy with autologous stem cell transplantation five-year results of a randomized trial on behalf of the GOELAMS group. Cancer 113(12):3323–3330 85. Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E et al (2014) Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 32(27):3059–3068 86. Hutchings M, Kostakoglu L, Zaucha JM, Malkowski B, Biggi A, Danielewicz I et al (2014) In vivo treatment sensitivity testing with positron emission tomography/computed tomography after one cycle of chemotherapy for Hodgkin lymphoma. J Clin Oncol 32(25):2705–2711 87. Straus DJ, Johnson JL, LaCasce AS, Bartlett NL, Kostakoglu L, Hsi ED et al (2011) Doxorubicin, vinblastine, and gemcitabine (CALGB 50203) for stage I/II nonbulky Hodgkin lymphoma: pretreatment prognostic factors and interim PET. Blood 117(20):5314–5320 D. Straus and M. Hertzberg 218 88. Radford J, Illidge T, Counsell N, Hancock B, Pettengell R, Johnson P et al (2015) Results of a trial of PET-directed therapy for early-stage Hodgkin’s lymphoma. N Engl J Med 372(17):1598–1607 89. Straus D, Pitcher B, Kostakoglu L, Grecula JC, Hsi ED, Schoder H et al (2016) Results of US intergroup trial of response-adapted chemotherapy or chemotherapy/radiation therapy based on PET for non-bulky stage I and II Hodgkin lymphoma (CALGB/ALLIANCE 50604) (Abstract). Haematol J Eur Hematol Assoc 101:13. ISHL 10. Journal of the European Hematology Association. 101. Cologne, Germany: Ferrata Storti Foundation 90. Raemaekers JM, Andre MP, Federico M, Girinsky T, Oumedaly R, Brusamolino E et al (2014) Omitting radiotherapy in early positron emission tomography- negative stage I/II Hodgkin lymphoma is associated with an increased risk of early relapse: clinical results of the preplanned interim analysis of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol 32(12):1188–1194 91. Andre MPE, Girinsky T, Federico M, Reman O, Fortpied C, Gotti M et al (2017) Early positron emission tomography response-adapted treatment in stage I and II Hodgkin lymphoma: final results of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol 35(16):1786–1794 92. Fuchs M, Goergen H, Kobe C, Eich H, Baues C, Greil R et al (2018) PET-guided treatment of early- stage favorable Hodgkin lymphoma: final results of the international, randomized phase 3 trial HD16 by the German Hodgkin Study Group. Blood 132(Suppl 1):925 93. Press OW, Li H, Schoder H, Straus DJ, Moskowitz CH, LeBlanc M et al (2016) US intergroup trial of response-adapted therapy for stage III to IV Hodgkin lymphoma using early interim fluorodeoxyglucose- positron emission tomography imaging: southwest oncology group S0816. J Clin Oncol 34(17):2020–2027 94. Borchmann P, Goergen H, Kobe C, Lohri A, Greil R, Eichenauer DA et al (2018) PET-guided treatment in patients with advanced-stage Hodgkin’s lymphoma (HD18): final results of an open-label, international, randomised phase 3 trial by the German Hodgkin Study Group. Lancet 390(10114):2790–2802 95. Connors JM, Jurczak W, Straus DJ, Ansell SM, Kim WS, Gallamini A et al (2018) Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin’s lymphoma. N Engl J Med 378(4):331–344 96. Ansell SM, Horwitz SM, Engert A, Khan KD, Lin T, Strair R et al (2007) Phase I/II study of an anti-CD30 monoclonal antibody (MDX-060) in Hodgkin’s lymphoma and anaplastic large-cell lymphoma. J Clin Oncol 25(19):2764–2769 97. Younes A, Romaguera J, Hagemeister F, McLaughlin P, Rodriguez MA, Fiumara P et al (2003) A pilot study of rituximab in patients with recurrent, classic Hodgkin disease. Cancer 98(2):310–314 98. Ekstrand BC, Lucas JB, Horwitz SM, Fan Z, Breslin S, Hoppe RT et al (2003) Rituximab in lymphocyte- 99. 100. 101. 102. 103. 104. 105. 106. 107. 108. 109. 110. predominant Hodgkin disease: results of a phase 2 trial. Blood 101(11):4285–4289 Mendler JH, Kelly J, Voci S, Marquis D, Rich L, Rossi RM et al (2008) Bortezomib and gemcitabine in relapsed or refractory Hodgkin’s lymphoma. Ann Oncol 19(10):1759–1764 Younes A, Pro B, Fanale M, McLaughlin P, Neelapu S, Fayad L et al (2007) Isotype-selective HDAC inhibitor MGCD0103 decreases serum TARC concentrations and produces clinical responses in heavily pretreated patients with relapsed classical Hodgkin lymphoma. Blood 110(11):2566 Bonadonna G, Santoro A, Bonfante V, Valagussa P (1982) Cyclic delivery of MOPP and ABVD combinations in stage IV Hodgkin’s disease: rationale, background studies, and recent results. Cancer Treat Rep 66(4):881–887 Radford JA, Crowther D, Rohatiner AZ, Ryder WD, Gupta RK, Oza A et al (1995) Results of a randomized trial comparing MVPP chemotherapy with a hybrid regimen, ChlVPP/EVA, in the initial treatment of Hodgkin’s disease. J Clin Oncol 13(9):2379–2385 Sutcliffe S, Wrigley PFM, Peto J, Lister TA, Stansfeld AG, Whitehouse JM et al (1978) MVPP chemotherapy regimen for advanced Hodgkin’s disease. Br Med J 6114:679–683 Selby P, Patel P, Milan S, Meldrum M, Mansi J, Mbidde E et al (1990) ChlVPP combination chemotherapy for Hodgkin’s disease: long-term results. Br J Cancer 62(2):279–285 Johnson PWM, Radford JA, Cullen MH, Sydes MR, Walewski J, Jack AS et al (2005) Comparison of ABVD and alternating or hybrid multidrug regimens for the treatment of advanced Hodgkin’s lymphoma: results of the United Kingdom lymphoma group LY09 trial (ISRCTN97144519). J Clin Oncol 23(36):9208–9218 Santoro A, Bonadonna G, Bonfante V, Valagussa P (1982) Alternating drug combinations in the treatment of advanced Hodgkin’s disease. N Engl J Med 306(13):770–775 Viviani S, Bonadonna G, Santoro A, Bonfante V, Zanini M, Devizzi L et al (1996) Alternating versus hybrid MOPP and ABVD combinations in advanced Hodgkin’s disease: ten-year results. J Clin Oncol 14(5):1421–1430 Sieber M, Tesch H, Pfistner B, Rueffer U, Paulus U, Munker R et al (2004) Treatment of advanced Hodgkin’s disease with COPP/ABV/IMEP versus COPP/ABVD and consolidating radiotherapy: final results of the German Hodgkin’s lymphoma study group HD6 trial. Ann Oncol 15(2):276–282 Aleman BM, Raemaekers JM, Tirelli U, Bortolus R (2003) T veer MB, Lybeert ML, et al. involved-field radiotherapy for advanced Hodgkin’s lymphoma. N Engl J Med 348(24):2396–2406 Klimo P, Connors JM (1985) MOPP/ABV hybrid program: combination chemotherapy based on early introduction of seven effective drugs for advanced Hodgkin’s disease. J Clin Oncol 3(9):1174–1182 Treatment of Early Favorable Hodgkin Lymphoma 11 Wouter Plattel and Pieternella Lugtenburg Contents 11.1 Introduction 219 11.2 11.2.1 11.2.2 efining Favorable Early-Stage Disease D Staging Prognostic Factors 220 220 221 11.3 Radiotherapy Alone 222 11.4 Late Treatment Effects and Mortality 223 11.5 11.5.1 11.5.2 11.5.3 11.5.4 11.5.5 Combined Modality Treatment Radiotherapy Alone Versus CMT Optimal Number of Cycles of Chemotherapy Optimal Chemotherapy Combination Optimal Radiation Dose Optimal Radiation Field Size 224 225 227 227 227 228 11.6 Chemotherapy Alone 230 11.7 Treatment Adaptation Based on PET Scan Response 230 11.8 Recommendations and Future Directions 234 References 234 11.1 W. Plattel (*) Department of Haematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands e-mail: w.j.plattel@umcg.nl P. Lugtenburg Department of Haematology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands Introduction Historically, Hodgkin lymphoma (HL) was the first malignant disease that could be cured. In the past century, the first successful outcomes of radiotherapy employing large radiation fields were reported, in particular, in patients with limited disease. Further refinement of this initial treatment approach was achieved through carefully designed prospective randomized phase III © Springer Nature Switzerland AG 2020 A. Engert, A. Younes (eds.), Hodgkin Lymphoma, Hematologic Malignancies, https://doi.org/10.1007/978-3-030-32482-7_11 219 W. Plattel and P. Lugtenburg 220 clinical trials. In this context, the step-by-step development of uniformly accepted staging procedures and clear definitions of stages and response criteria was a major achievement. This allowed direct comparison of study results performed in different consortia worldwide. Focusing on stage-adapted treatment of HL, these trials allowed the definition of clinical prognostic factors. These, in turn, lead to risk-adapted treatment, which became more refined with subsequent studies. In line with these advances, treatment strategies changed from radiotherapy only using extended-field radiotherapy (EFRT) and later involved-field radiotherapy (IFRT) to combined modality treatment (CMT) with rather small radiotherapy fields and chemotherapy exposure. Thanks to the long-term follow-up of thousands of patients treated within clinical trials over decades, significant late effects of treatment became apparent. The higher mortality rate in HL survivors turned out to be mainly due to secondary malignancies and damage to the cardiovascular and respiratory systems. Based on these unexpected findings, the ingredients of curative regimens were further adjusted. As far as possible, noncarcinogenic cytostatic agents were introduced in newly developed chemotherapy regimens, and radiation doses were further reduced. This has led to the current major challenges in the treatment of early-stage HL: maintaining the very high cure rates and at the same time reducing the incidence of early and late toxicity. To further improve on this strategy, it is strongly advocated to treat early-stage HL patients within clinical trials. This chapter deals with past and recent developments in the treatment of stage I and II HL with favorable prognostic factors comprising about 40% of all early-stage HL patients. 11.2 efining Favorable Early- D Stage Disease 11.2.1 Staging In HL patients, prognosis is distinctly worse with each progressive stage of disease, and the selection of appropriate treatment depends on accurate staging of the extent of disease. The Ann Arbor staging classification was formulated in 1971 and is still the most commonly used staging system for HL [1]. During the Cotswold meeting in 1989, some modifications were introduced to account for new imaging techniques such as computerized tomography (CT) scanning. In addition, clinical involvement of the liver and spleen was redefined, to formally introduce the concept of bulky disease and to draw the attention to the problem of equivocal complete remission [2]. Stage I indicates involvement of a single lymph node region or a single extranodal organ or site. In stage II disease, two or more lymph node regions on the same side of the diaphragm are involved, or there is localized involvement of an extranodal organ or site and of one or more lymph node regions on the same side of the diaphragm. The stage number is followed by the suffix A or B indicating the absence (A) or presence (B) of one or more of the following constitutional symptoms: (a) unexplained fever with temperatures above 38 °C during the previous month, (b) drenching night sweats during the previous months, and (c) unexplained weight loss of more than 10% of body weight in the previous 6 months. Mediastinal bulk was defined by the ratio of the maximum transverse tumor diameter to the internal thoracic diameter at the level of the T5–T6 vertebral interspace. A ratio exceeding one-third was considered bulky. For the initial staging of HL, a detailed history, complete physical examination, and imaging studies with whole body positron emission tomography using [18F]-fluoro-2-deoxy-dglucose (FDG-PET, here referred to as PET) scanning and CT scans of the neck, thorax, abdomen, and pelvis are generally recommended [3, 4]. In patients with PET-CT-assessed HL, bone marrow biopsy can be omitted [5]. See Chaps. 6 and 7 for a more comprehensive review of clinical evaluation and functional imaging. About 8% of stage I–II HL patients present with infradiaphragmatic disease [6, 7]. Patients with infradiaphragmatic HL are generally older, more frequently male, have poorer performance status, and present less frequently with nodular 11 Treatment of Early Favorable Hodgkin Lymphoma 221 Table 11.1 Definition of early-stage favorable HL EORTC–GELA CS I–II without risk factors (supradiaphragmatic): – No large mediastinal mass – Age <50 years – No elevated ESRa – 1–3 involved nodal regions GHSG CS I–II without risk factors: – No large mediastinal mass – No extranodal disease – No elevated ESRa – 1–2 involved nodal regions NCI-C/ECOG CS I–IIA without risk factors (supradiaphragmatic): – No large mediastinal mass – Age <40 years – ESR <50 mm/h – 1–3 involved nodal regions – LPHL or NS histology EORTC European Organization for Research and Treatment of Cancer, GELA Groupe d’Etude des Lymphomes de l’Adulte, GHSG German Hodgkin Study Group, NCI-C National Cancer Institute of Canada, ECOG Eastern Cooperative Oncology Group, CS clinical stage, ESR erythrocyte sedimentation rate, LPHL nodular lymphocyte-predominant Hodgkin lymphoma, NS nodular sclerosis a ESR <50 mm/h without B symptoms or ESR <30 mm/h with B symptoms sclerosis subtype compared to patients with supradiaphragmatic disease. Furthermore, these patients have a significantly poorer progression- free survival (PFS) and overall survival (OS) as compared to patients with supradiaphragmatic disease [7]. Therefore, these patients should be considered as early unfavorable HL which is further described in Chap. 12. 11.2.2 Prognostic Factors Historically, several studies describing prognostic factors in early-stage HL have been performed [8, 9] to predict for occult disease in the abdomen and effectiveness of treatment. They were derived from long-term follow-up of patient cohorts treated in a variety of phase III prospective randomized trials. The prognostic significance of bulky disease particularly in the mediastinum, the presence of constitutional symptoms, the erythrocyte sedimentation rate (ESR), and the number of involved lymph node regions were uniformly included in clinically applied prognostic models (see Chap. 8 for prognostic factors). Different Lymphoma Collaborative Groups worldwide use varying combinations of prognostic factors to identify prognostic risk groups. These prognostic factors allow patients to be stratified into favorable or unfavorable prognostic groups. The current definitions of a favorable treatment group according to the different study groups in Europe and the United States are presented in Table 11.1. The Lymphoma Group of the European Organization for Research and Treatment of Cancer (EORTC) and the French– Belgian Groupe d’Etude des Lymphomes de l’Adulte (GELA) define clinical stage I–II patients as favorable if they present with the following characteristics: age <50 years and low ESR (<50 mm/h without and <30 mm/h with B symptoms), no more than three involved lymph node regions, and no large mediastinal mass [10]. All these criteria need to be met to be “favorable.” The German Hodgkin Study Group (GHSG) criteria differ slightly in that they substituted age <50 years with no extranodal disease and specify no more than two involved nodal regions rather than ≤3 as in the EORTC [11]. In Canada and North America, it is common to define an early or limited stage risk group as stage I and IIA disease without bulky disease (see Table 11.1). Many of these defined risk factors are reflective of or correlate with disease burden. Currently applied PET/CT imaging for staging of HL allows accurate measurement of total metabolic tumor volume (TMTV). The prognostic value of TMTV has been increasingly described in HL. In early-stage HL, a retrospective analyses of TMTV of staging PET/CT images from the EORTC/GELA/FIL H10 showed that TMTV outperforms the classical risk factors described above in terms of prediction of interim PET W. Plattel and P. Lugtenburg 222 p ositivity and PFS [12]. However, standardization of measurement of TMTV is the major challenge before clinical application. 11.3 Radiotherapy Alone The use of radiation therapy, pioneered at Stanford University in the 1960s by Henry Kaplan and Saul Rosenberg, offered HL patients the first hope for cure. In the treatment of early stages, EFRT was considered the standard treatment modality for many years. With this technique, radiation was delivered not only to the clinically involved but also to the adjacent, clinically uninvolved sites. Because it was known that HL spreads to contiguous nodal sites, mantle field RT encompassed all nodal sites above the diaphragm. The combination of mantle field with inverted-Y field and spleen irradiation was termed “subtotal nodal irradiation” (STNI). See Chap. 9 for definitions of field size. Significant advances in the treatment of HL were then derived from clinical trials. Investigators at Stanford demonstrated that radiation therapy alone using total lymphoid irradiation or STNI is an adequate treatment for nearly all patients with pathologic stages I–II. In a series of 109 patients, the freedom from relapse rate at 10 years was 77% [13]. A retrospective study from Canada studied the impact of patient selection and EFRT on outcome among patients with clinical stages I and II treated between 1978 and 1986. Patients with favorable prognostic features (age <50 years, ESR <40 mm/h, and lymphocytepredominant or nodular sclerosing histology) treated with mantle and para-aortic-splenic irradiation had only 12.7% actuarial risk of relapse at 8 years [14]. Between 1964 and 1987, the EORTC performed four consecutive randomized clinical trials aiming to delineate the subsets of patients with stage I and II disease who could be safely treated with RT alone [15, 16] (Table 11.2). Taken together, these four randomized trials demonstrated that staging laparotomy could be safely omitted in patients with favorable clinical characteristics in early favorable HL and that these patients could be treated by STNI (40 Gy) with a similar outcome as obtained by staging laparotomy followed by mantle field RT (40 Gy). Another important finding was that the overall outcome had gradually improved over the years (Fig. 11.1). The total radiation dose in these EORTC trials was always 40 Gy. The GHSG HD4 trial showed that patients without risk factors had similar outcomes when treated with 40 Gy radiaton to the involved field and 30 Gy to the non-involved extended field [22]. The 7-year relapse-free and overall survival rates were 78% vs. 83% and 91% vs. 96%, respectively. Radiation in mantle field technique was expected to cause less long-term toxicity compared with STNI. However, in clinically staged patients, results with mantle field irradiation alone have been disappointing. In the EORTC H7-VF and H8-VF trials, 40 female patients were treated with mantle field RT only. The respective prognostic factors were stage IA, age <40 years, nodular sclerosing or lymphocyte-predominant histology, and ESR <50 mm/h. These patients were expected to have a very low risk of occult abdominal involvement (5%). The relapse-free survival was however lower than expected: a total of 23% had relapsed at 6 years [21]. Because of this unacceptable rate, the very favorable subgroup has since been treated according to the EORTC strategy for the favorable subgroup. Specht et al. reported on the influence of radiation field size on long-term outcome in early-stage disease in a meta-analysis of eight randomized trials evaluating larger vs. smaller radiation fields [23]. These trials included almost 2000 patients with both, favorable and unfavorable prognosis stage I–II disease. A definite and substantial reduction in the risk of treatment failure was demonstrated if more extensive radiotherapy was used. The 10-year risk of recurrence was 43% for patients treated with smaller-field irradiation compared to 31% for those treated with larger-field radiation therapy. Although the additional radiotherapy prevented a substantial proportion of recurrences, it did not significantly affect overall 11 Treatment of Early Favorable Hodgkin Lymphoma 223 Table 11.2 Early-stage favorable HL: selection of randomized studies of radiotherapy alone Number of patients Outcome 288 A. 38% DFS (15 years) B. 60% DFS (15 years) p < 0.001 Trial EORTC HI Year 1964–1971 Study arms A. M antle field or inverted-Y RT B. The same RT followed by vinblastine EORTC H2 1972–1976 A. Laparotomy and mantle field + Para-aortic lymph node RT B. STNI 300 Laparotomy negative patients A. Mantle field RT 198 EORTC H5F 1977–1982 B. STNI EORTC H6F EORTC H7VF- H8VF GHSG HD4 1982–1987 A. Laparotomy, if negative: Mantle field RT for LP or NSc histology STNI for MC or LD histology B. STNI 262 1988–1993 Mantle field RT 40 1988–1994 A. STNI 40 Gy 376 B. STNI 30 Gy + IFRT 10 Gy A. 76% DFS (12 years) Overall survival A. 58% OS (15 years) B. 65% OS (15 years) p = 0.15 (NS) A. 79% OS (12 years) B. 68% DFS (12 years) p = 0.18 (NS) A. 69% DFS (9 years) B. 70% DFS (9 years) p > 0.50 (NS) A. 84% RFS (6 years) B. 77% OS (12 years) p = 0.38 (NS) A. 94% OS (9 years) B. 91% OS (9 years) p > 0.50 (NS) A. 89% OS (6 years) Carde et al. [20] B. 80% RFS (6 years) p = 0.25 (NS) RFS 73% (6 years) B. 93% OS (6 years) p = 0.24 (NS) OS 95% (6 years) Noordijk et al. [21] A. 78% RFS (7 years) B. 83% RFS (7 years) p = 0.093 (NS) A. 91% OS (7 years) B. 96% OS (7 years) p = 0.16 (NS) Reference Tubiana et al. [17] Tubiana et al. [16, 18] Carde et al. [19] Dühmke et al. [22] EORTC European Organization for Research and Treatment of Cancer, GHSG German Hodgkin Study Group, DFS disease-free survival, OS overall survival, RFS relapse-free survival, STNI subtotal nodal irradiation, RT radiotherapy, IFRT involved-field radiotherapy, Gy Gray, NS not significant, LP lymphocyte predominant, NSc nodular sclerosing, MC mixed cellularity, LD lymphocyte depleted mortality. The lack of survival difference suggests that salvage chemotherapy for relapse after initial radiotherapy is effective enough to minimize the impact of any increase in relapse on survival. To summarize, STNI was considered a standard treatment for early favorable HL until the 1990s. However, 25–30% of patients eventually relapsed with subsequent 10-year survival rates of only 63% [24]. 11.4 Late Treatment Effects and Mortality As the number of patients surviving HL increased and there was longer follow-up, it became evident that their life expectancy did not revert to that of the age-matched general population. The higher mortality of HL patients is largely a result of the long-term effects of treatment. Important late effects comprise secondary malignancies, W. Plattel and P. Lugtenburg 224 Fig. 11.1 Disease-free survival and overall survival in consecutive EORTC Lymphoma Group trials on early-stage favorable Hodgkin lymphoma (HL). DFS disease-free survival, OS overall survival 100 80 60 40 20 0 H1 H2 DFS H5F H6F H7F H8F OS cardiovascular diseases, pulmonary problems, gonadal dysfunction, infectious complications, and fatigue. The incidence of the most life- threatening late side effects, i.e., secondary cancers and cardiovascular diseases, is significantly related to the radiation dose and field size, choice of cytostatic drugs, and total amount of drugs administered. In patients with early favorable disease, mortality from causes other than HL has increased over time, exceeding HL-related mortality after 10–15 years [25, 26]. A large study with a median follow-up of more than 17 years examined case- specific mortality and absolute excess mortality, compared to population rates, in a cohort of 1261 Dutch patients [25]. These patients were younger than 40 years when treated between 1965 and 1987. HL was the most frequent cause of death (55%), followed by secondary malignancies (22%) and cardiovascular diseases (9%). In the first 10 years following initial treatment, the excess mortality rate was largely due to the primary disease, while after 10 years, causes other than HL contributed most to excess mortality. The actuarial risk of death is shown in Fig. 11.2. Even after 30 years of follow-up, there was no evidence of a decline in the relative risk of death from causes other than HL. In 30-year survivors, the annual excess mortality rate from all causes other than HL was nearly 3 per 100 patients. Solid tumors, especially in the digestive and respiratory tract, contributed most to this excess risk, followed by cardiovascular diseases [25]. In 2009, the EORTC and the GELA published their results of a study analyzing the cause-specific excess mortality in adult patients with respect to treatment modality [27]. The study population consisted of 4401 patients aged 15–69 in all stages, who were treated between 1964 and 2000. In patients with early-stage disease, the overall excess mortality was associated with age ≥40 years (p = 0.007), male gender (p < 0.001), unfavorable prognostic features (p < 0.001), treatment with EBVP (epirubicin, bleomycin, vinblastine, prednisone) plus IFRT (p = 0.002), and mantle field irradiation alone (p = 0.003). Therefore, excess mortality was linked to treatment modalities that were associated with poor failure-free survival resulting in a higher need for salvage treatment. Late treatment effects are covered in more detail in Chaps. 26–29. 11.5 Combined Modality Treatment With the observation of high relapse rates and fatal long-term effects, most study groups abandoned STNI and EFRT from the treatment of early-stage HL. Studies were developed in an Treatment of Early Favorable Hodgkin Lymphoma Fig. 11.2 The actuarial risks of death from major disease categories in 1261 Dutch HL patients. Data from Dutch database on Hodgkin lymphoma (Reprinted from Aleman et al. [25] with permission) 225 50 Cumulative risk of death (%) 11 Cause of death 40 Hodgkin’s disease 30 Other than HD 20 Second cancer 10 Cardiovascular disease 0 0 5 10 15 20 30 25 35 Follow-up (years) Numbers at risk 1,032 918 attempt to reduce long-term toxicity without increasing disease-specific mortality. Most randomized studies evaluated CMT in an attempt to define the optimal chemotherapy, number of cycles needed, as well as radiation field size and dose when combined with chemotherapy. Commonly used regimen and drug combinations are listed in Table 11.3. 796 High relapse rates after treatment with radiotherapy alone prompted several groups to study CMT as induction therapy. An earlier meta-analysis of individual patient data showed that CMT reduced the relapse risk compared with radiotherapy alone, but did not improve overall survival [23]. Most of the trials included in this analysis were conducted between 1967 and 1988 using MOPP or MOPP-like regimens, which produced unacceptable hematologic toxicity, frequently induced secondary malignancies, and rendered most recipients infertile. These studies are therefore only of historical interest and will not be discussed further. Later, based mainly on results of studies in advanced HL, the ABVD regimen became the standard of care in early favorable 272 100 Table 11.3 Chemotherapy regimens used in early-stage favorable HL Regimen ABVD EBVP MOPP MOPP– ABV 11.5.1 Radiotherapy Alone Versus CMT 513 Stanford V VBM Drug combinations Doxorubicin, vinblastine, bleomycin, dacarbazine Epirubicin, bleomycin, vinblastine, prednisone Mechlorethamine, vincristine, procarbazine, prednisone Mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine Vinblastine, doxorubicin, vincristine, bleomycin, mechlorethamine, etoposide, prednisone Vinblastine, methotrexate, bleomycin HL. When compared with MOPP, ABVD had a better efficacy and produced less toxicity [28]. In particular, secondary leukemias and infertility were less frequently observed than after alkylating agent-containing regimens. Two randomized studies, one in Germany and one in the United States, showed the benefit of adjuvant chemotherapy with a short course of ABVD or ABVD-like chemotherapy in early favorable patients: the GHSG HD7 trial compared EFRT alone with CMT consisting of two cycles of ABVD followed by EFRT in early favorable patients [11]. A significant advantage W. Plattel and P. Lugtenburg 226 in freedom from treatment failure (FFTF) was seen after CMT, mainly related to fewer relapses as compared with EFRT only (3% vs. 22%). There were no differences in overall survival between treatment arms. Importantly, CMT was not associated with significantly more acute or long-term toxicity. A trial from the United States confirmed the benefit of a short course of limited chemotherapy added to STNI in clinically staged IA and IIA patients [29]. The study showed that three cycles of doxorubicin and vinblastine (AV) followed by STNI were well tolerated and gave a superior failure-free survival compared with STNI alone. The conclusion from these two studies is that the number of relapses can be reduced by the addition of ABVD or ABVD-like chemotherapy to large radiation fields. However, long- term toxicity was still of concern due to the use of extensive radiation fields. The Group Pierre-et-Marie-Curie showed that it was possible to replace the classic mantle field irradiation with a more limited radiotherapy to initially involved areas only. This novel approach termed IFRT involved the addition of chemotherapy to control occult disease in uninvolved areas [31]. IFRT reduced the irradiation of normal tissues, such as the breast, heart, and lungs. Therefore, several groups performed randomized trials comparing STNI with a combined modality approach in which patients received smaller radiation fields and combination chemotherapy. The results of a selection of some of the largest trials are listed in Table 11.4. Table 11.4 Early-stage favorable HL: selection of studies comparing STNI alone with combined modality treatment (CMT) Trial SWOG/CALGB Year 1989– 2000 Study arms A. STNI (36–40 Gy) B. 3 AV + STNI (36–40 Gy) Stanford–Kaiser Permanente 1988– 1995 A. STNI (30–44 Gy) B. 6 VBM + mantle field RT EORTC H7F 1988– 1993 A. STNI (36 Gy) B. 6 EBVP + IFRT (36 Gy) EORTC–GELA H8F GHSG HD7 1993– 1999 1994– 1998 A. STNI (36 Gy) B. 3 MOPP– ABV + IFRT (36 Gy) A. EFRT 30 Gy (IFRT 40 Gy) B. 2 ABVD + EFRT 30 Gy (IFRT 40 Gy) Number of patients Outcome 326 A. 81% FFS (3 years) B. 94% FFS (3 years) p < 0.001 78 A. 92% PFS (5 years) B. 87% PFS (5 years) p = 0.73 (NS) 333 A. 78% EFS (10 years) B. 88% EFS (10 years) p = 0.0113 542 A. 68% EFS (10 years) B. 93% EFS (10 years) p < 0.001 627 A. 67% FFTF (7 years) B. 88% FFTF (7 years) p < 0.0001 Overall survival Follow-up too short A. 98% OS (5 years) B. 94% OS (5 years) p = 0.05 (NS) A. 92% OS (10 years) B. 92% OS (10 years) p = 0.79 (NS) A. 92% OS (10 years) B. 97% OS (10 years) p = 0.001 A. 92% OS (7 years) B. 94% OS (7 years) p = 0.43 (NS) Reference Press et al. [29] Horning et al. [30] Noordijk et al. [32] Fermé et al. [10] Engert et al. [11] SWOG Southwest Oncology Group, CALGB Cancer and Leukemia, EORTC European Organization for Research and Treatment of Cancer, GELA Groupe d’Etude des Lymphomes de l’Adulte, GHSG German Hodgkin Study Group, STNI subtotal nodal irradiation, IFRT involved-field radiotherapy, EFRT extended-field radiotherapy, Gy Gray, FFS failure- free survival, PFS progression-free survival, EFS event-free survival, FFTF freedom from treatment failure, OS overall survival, NS not significant 11 Treatment of Early Favorable Hodgkin Lymphoma 227 In the EORTC H7F trial, patients with early favorable disease were treated with six cycles of EBVP followed by IFRT or STNI [32]. The 10-year event-free survival rate after EBVP and IFRT was 10% better than after STNI alone, whereas overall survival was 92% in both arms. This trial demonstrated that EFRT could be replaced by CMT including IFRT. However, in early unfavorable patients, EBVP was significantly less efficient than MOPP–ABV [32]. In the subsequent H8F trial by the EORTC– GELA, favorable HL patients were randomized between STNI or CMT consisting of three cycles of MOPP–ABV hybrid followed by IFRT [10]. Patients in the CMT arm had a lower relapse rate, which resulted in a significantly higher event-free survival rate than for patients in the STNI arm (93% vs. 68% at 10 years). Importantly, patients in the combined modality arm also had a significantly higher overall survival (97% vs. 92% at 10 years). The results of this study again demonstrated the superiority of CMT over EFRT alone and showed that IFRT is a sufficient treatment after chemotherapy for early favorable HL. However, due to its carcinogenic potential, MOPP–ABV was abandoned in favor of ABVD. difference between 30 and 20 Gy IFRT [33]. Importantly, there was also no significant difference in terms of overall survival, FFTF, and progression-free survival when all four arms were compared. The results were robust with longer follow-up (8 years). The treatment arms with four cycles of ABVD and 30 Gy IFRT showed significantly more acute toxicity in comparison with two cycles of ABVD and 20 Gy IFRT. Two cycles of ABVD followed by 20 Gy IFRT are thus GHSG standard of care for HL patients in early favorable stages. 11.5.2 O ptimal Number of Cycles of Chemotherapy The use of fewer cycles of ABVD could potentially reduce late side effects of combined modality therapy. Between 1998 and 2003, the GHSG HD10 trial accrued more than 1300 favorable prognosis stage I–II HL patients. Patients were randomized to four arms in a 2 × 2 factorial design: two cycles of ABVD followed by 30 Gy IFRT, two cycles of ABVD followed by 20 Gy IFRT, four cycles of ABVD followed by 30 Gy IFRT, and four cycles of ABVD followed by 20 Gy IFRT. This trial tested a possible reduction in the number of ABVD cycles as well as reduction of radiation dose when using IFRT. With a median follow-up of 90 months, there were no significant differences in FFTF and overall survival at 5 years between four or two cycles of ABVD. In addition, there was also no 11.5.3 Optimal Chemotherapy Combination Reduction of chemotherapy-induced toxicity was pursued in the GHSG HD13 trial. This trial investigated whether drugs can be omitted from the ABVD regimen and randomized patients with early favorable HL to two cycles of either ABVD, AVD, ABV, or AV with all arms followed by 30 Gy IFRT. Compared with ABVD, the 5-year FFTF was reduced up to 11.7% (ABV) or 16% (AV) when dacarbazine and dacarbazine and bleomycin were deleted and reduced up to 3.9% (AVD) by the deletion of bleomycin. The reduction in FFTF did not translate into poorer OS [34]. Therefore, it seems that particularly dacarbazine and to a lesser extent bleomycin are relevant therapeutic agents in ABVD. The Stanford group has reported good results in 87 patients with stage I or IIA non-bulky HL treated with an abbreviated Stanford V regimen administered weekly for 8 weeks followed by 30 Gy modified IFRT [35]. At a median follow-up of 10 years, the FFP was 94%. 11.5.4 Optimal Radiation Dose Apart from the choice of cytostatic agents and the number of courses, the question of radiation field size and dose has also been evaluated (for a selection of randomized trials, see Table 11.5). A decline in late complications is expected with lower radiation doses as their incidence is directly W. Plattel and P. Lugtenburg 228 Table 11.5 Early-stage favorable HL: selection of studies of RT field size and dose in CMT Trial Milan Year 1990– 1997 EORTC– GELA H9F 1998– 2004 Study arms A. 4 ABVD + STNI 36–40 Gy B. 4 ABVD + IFRT 36–40 Gy A. 6 EBVP + IFRT 36 Gy B. 6 EBVP + IFRT20 Gy C. 6 EBVP (no RT) Number of patients 133 783 Median follow-up 33 months GHSGHD10 1998– 2003 A. 2 ABVD + IFRT 30 Gy B. 2 ABVD + IFRT 20 Gy C. 4 ABVD + IFRT 30 Gy D. 4 ABVD + IFRT 20 Gy Median follow-up 91 months 1.370 Outcome A. FFP 93% (12 years) B. FFP 94% (12 years) A. EFS 87% (4 years) B. EFS 84% (4 years) C. EFS 70% (4 years) No RT arm closed because of excess failure rate (p < 0.001) No differences in FFTF between patients given two or four cycles of ABVD or 20 or 30 Gy IFRT (FFTF 91–93%) Overall survival A. OS 96% (12 years) B. OS 94% (12 years) A. OS 98% (4 years) B. OS 98% (4 years) C. OS 98% (4 years) Reference Bonadonna et al. [36] No survival differences between patients given two or four cycles of ABVD or 20 or 30 Gy IFRT (OS 96–97%) Engert et al. [33] Noordijk et al. [37] EORTC European Organization for Research and Treatment of Cancer, GELA Groupe d’Etude des Lymphomes de l’Adulte, GHSG German Hodgkin Study Group, STNI subtotal nodal irradiation, IFRT involved-field radiotherapy, RT radiotherapy, Gy Gray, FFP freedom from progression, OS overall survival, EFS event-free survival, FFTF freedom from treatment failure correlated with the dose of radiation administered. Two randomized trials have investigated radiation doses in early favorable HL patients treated with CMT. In the EORTC–GELA H9F trial, 783 patients with stage I–II disease and favorable characteristics received six cycles of EBVP. Patients in complete remission after chemotherapy were randomized to receive standard dose IFRT (36 Gy), low-dose IFRT (20 Gy), or no RT at all. The experimental arm without RT was closed early due to an excess failure rate compared with the two RT arms, but there were no differences in outcome reported between the two radiation dose levels. As discussed in Sect. 11.5.2, the GHSG HD10 trial compared doses of 30 and 20 Gy IFRT after two or four cycles of ABVD. No significant differences were observed between patients receiving 30 Gy IFRT and 20 Gy IFRT in terms of overall survival (97.7 vs. 97.5%), FFTF (93.4 vs. 92.9%), and progression-free survival (93.7 vs. 93.2%), respectively [33]. Therefore, IFRT with a dose of 20 Gy seems to be sufficient after two cycles of ABVD. 11.5.5 Optimal Radiation Field Size The rationale for reduced radiation therapy field size is to decrease potential late complications such as cardiovascular and secondary cancers as the amount of irradiated normal tissue is reduced. Several randomized trials in early unfavorable HL have shown that after effective chemotherapy, IFRT is as effective as EFRT in terms of overall survival and FFTF [10, 38]. However, data from 11 Treatment of Early Favorable Hodgkin Lymphoma 229 randomized trials in patients with early favorable HL are scarce. Bonadonna et al. reported the long-term follow-up of 133 patients with early HL randomly assigned to IFRT or STNI after four cycles of ABVD and found no significant differences in overall survival (94 vs. 96%) or freedom from progression (94 vs. 93%) at 12 years [36] (see Table 11.5). The limited size of the patient sample, however, had no adequate statistical power to test for non-inferiority of IFRT vs. STNI. The EORTC–GELA group introduced the concept of involved-node radiotherapy (INRT) to further decrease the radiotherapy fields [39, 40]. INRT only includes the initially involved lymph nodes with a small isotropic margin. Identifying and contouring involved lymph nodes is of outmost importance. Therefore, it is recommended that all patients have cervical and thoracic CT scans pre- and post-chemotherapy, preferably in the radiotherapy position, and must be examined by the radiation oncologist before the start of the chemotherapy [39, 41]. Better sparing of normal tissues such as the salivary glands, heart, coronary arteries, and breast in female patients is expected with the use of INRT compared to IFRT (Fig. 11.3). The new INRT concept was applied in the EORTC–GELA–FIL H10 randomized trial for patients with earlystage HL. As is shown later in this chapter, INRT was associated with higher PFS rates compared to no radiotherapy. a c b d Fig. 11.3 Comparison between radiation field sizes and the volume of heart irradiation using either IFRT (a, b) or INRT (c, d) for a mediastinal tumor mass (PTV in red color) (Reprinted from Girinsky et al. [39] with permission) W. Plattel and P. Lugtenburg 230 Canadian researchers reported promising results with INRT in a retrospective study, although a greater radiation margin was applied as in the EORTC–GELA–FIL H10 trial [42]. In British Columbia, the extent of the radiation therapy field size underwent serial changes during the last decades, from EFRT to IFRT and eventually since 2001 to INRT with margins from 1.5 to 5 cm. There were no statistically significant differences among the three groups for PFS and overall survival. There were also no marginal recurrences in the INRT patient group [42]. Although the exact definition of INRT needs further standardization, the concept of INRT seems feasible. 11.6 Chemotherapy Alone The potentially life-threatening late side effects of radiotherapy for HL patients have raised the question whether those in early-stage disease can be treated with chemotherapy alone. This question is particularly relevant for patients in whom the risk of RT-induced toxicity is deemed less acceptable. Chemotherapy-only protocols have been successfully used in children and adolescents (see Chap. 14 on pediatric HL). However, few data exist on their role in adults. Table 11.6 shows a selection of randomized trials performed in adult patients with early favorable HL dealing with the issue of chemotherapy alone. These trials encountered a number of problems with design, patient accrual, as well as variations in the type of chemotherapy and field size of radiation therapy utilized. The use of chemotherapy alone is not a new concept. In the early 1990s, two trials comparing MOPP with radiotherapy as first-line therapy in early-stage HL were published [43, 44]. Long relapse-free survival varied from 70% to 80%, with varying outcomes of salvage chemotherapy. The National Cancer Institute of Canada (NCI-C) and the Eastern Cooperative Oncology Group (ECOG) conducted a randomized phase III trial addressing the role of ABVD alone for early favorable and unfavorable HL. The experimental arm consisted of four cycles of ABVD alone if a complete remission was achieved after two cycles. Otherwise, patients received six cycles. The standard arm was STNI with 36 Gy. Among the favorable-risk patients, there was no difference between the two arms for event-free survival, freedom from disease progression, and overall survival after a median follow-up of 11.3 years [45]. However, even longer follow-up is still needed to determine late toxicities. Only two randomized trials comparing CMT with chemotherapy alone in early favorable patients have been published. As discussed in Sect. 11.5.4, one was the EORTC–GELA H9F trial in which IFRT in 36 Gy was compared with 20 Gy or no radiotherapy in CR patients after six cycles of EBVP. The chemotherapy-only arm was prematurely closed due to an excessive number of relapses [37]. The Memorial Sloan Kettering Cancer Center randomized early non-bulky HL patients between six cycles of ABVD alone and six cycles of ABVD plus 36 Gy radiotherapy. Due to the poor accrual rate, the trial was closed before completion, and only 152 patients were randomized. No significant differences were observed between CMT and chemotherapy alone, but the sample size was insufficient [46]. 11.7 reatment Adaptation Based T on PET Scan Response Functional imaging with PET scanning has become the standard tool for staging and response assessment in HL (see Chap. 7). Interim PET scanning enables evaluation of early metabolic changes rather than the morphologic changes occurring later during and after treatment. Several studies using PET after two or three cycles of ABVD have shown that early metabolic changes are predictive of the final treatment response and PFS [47–51]. Based on these studies which were mainly performed among advanced stage patients, several cooperative groups incorporated interim PET imaging in their early-stage trials to reduce treatment exposure in responding patients to prevent overtreatment and/or intensify treatment in case of nonresponsiveness [52–54]. A 11 Treatment of Early Favorable Hodgkin Lymphoma 231 Table 11.6 Early-stage favorable HL: selection of randomized studies of chemotherapy alone in adult patients Trial NCI-US Year 1978– 1989 Study arms A. 6–8 MOPP B. Radiotherapy Rome– Florence NCI-C/ECOG HD6 1979– 1982 1994– 2002 A. Mantle field + Para-aortic RT (36–44 Gy) B. 6 MOPP A. 4–6 ABVD Number of patients Outcome 84 A. DFS 82% (10 years) B. DFS 67% (10 years) p = NS 89 A. RFS 70% (8 years) B. RFS 71% (8 years) 123 B. STNI EORTC– GELA H9F 1998– 2004 A. 6 EBVP + IFRT 36 Gy B. 6 EBVP + IFRT 20 Gy C. 6 EBVP (no RT) B. EFS 88% (5 years) 783 1990– 2000 A. 6 × ABVD p = 0.6 (NS) A. EFS 87% (4 years) B. EFS 84% (4 years) Median follow-up 33 months Memorial Sloan Kettering Cancer center p = NS A. EFS 87% (5 years) 152 B. 6 × ABVD + RT Overall survival A. OS 90% (10 years) B. OS 85% (10 years) p = NS A. OS 93% (8 years) B. OS 56% (8 years) p < 0.001 A. OS 97% (5 years) B. OS 100% (5 years) p = 0.3 (NS) A. OS 98% (4 years) B. OS 98% (4 years) C. OS 98% (4 years) C. EFS 70% (4 years) No RT arm closed because of excess failure rate (p < 0.001) A. FFP 81% (5 years) A. OS 90% (5 years) B. FFP 86% (5 years) B. OS 97% (5 years) p = 0.61 (NS) p = 0.08 (NS) Reference Longo et al. [43] Biti et al. [44] Meyer et al. [45] Noordijk et al. [37] Strauss et al. [46] NCI-US National Cancer Institute United States, EORTC European Organization for Research and Treatment of Cancer, NCI-C National Cancer Institute of Canada, ECOG Eastern Cooperative Oncology Group, GELA Groupe d’Etude des Lymphomes de l’Adulte, STNI subtotal nodal irradiation, IFRT involved-field radiotherapy, RT radiotherapy, Gy Gray, NS not significant, FFP freedom from progression, OS overall survival, DFS disease-free survival, RFS relapse-free survival, EFS event-free survival summary of the results of these large randomized trials are displayed in Table 11.7 and Fig. 11.4. In the NCI rapid trial, patients with stage IA or IIA non-bulky HL were treated with three cycles of ABVD after which PET scanning was performed. The PET scan was negative in 426 out of 602 patients (75%). These 426 patients were randomized between no further treatment and IFRT. In the intention-to-treat analysis, the PFS after 3 years in the no further treatment arm was 90.8% versus 94.6% in the IFRT arm. Because of the large numbers of cross-overs in this trial, the per protocol analysis is also of interest. In this analysis, PFS was 90.8% versus 97.1% in the arm including IFRT [52]. The EORTC/GELA/FIL H10 trial with a total of 1950 randomized patients also investigated chemotherapy-only strategies in case of interim PET negativity. In this trial, patients with early favorable disease were treated in the standard arm with three cycles of ABVD and 30 Gy INRT. An interim PET scan was performed after two cycles, but no treatment change was performed on the basis of this scan. In the experimental arm, there was both a de-escalation non-inferiority question in case of a negative interim PET scan and an escalating superiority question in case of a positive interim PET scan. In patients with negative PET findings, INRT was substituted by a single extra cycle of ABVD in W. Plattel and P. Lugtenburg 232 Table 11.7 Results of PET response-adapted early favorable Hodgkin lymphoma trials focusing at de-escalation by leaving out radiotherapy: EORTC H10-F, UK RAPID and GHSG HD16trials Trial UK RAPID trial Year 2003– 2010 EORTC H10-F 2006– 2011 GHSG HD16 2009– 2015 Study arms 3 ABVD if PET negative followed by: A. 30 Gy IF-RT B. No further treatment 2 ABVD if PET negative followed by: A. 3×ABVD + IN-RT B. 4×ABVD (no radiotherapy). 2 ABVD if PET negative followed by: A. 20 Gy IF-RT B. No further treatment Number of patients 426 Overall survival At 3 years A. 97.1% B. 99%. Outcome PFS at 3 years (per protocol analysis) A. 97.1% B. 90.8%. PFS at 5 years: A. 99% B. 87.1% 1950 1150 PFS at 5 years: A. 93.4% B. 86.1%. Reference Radford et al. [52] At 5 years: A. 100 B. 99.6%. Andre et al. [53] At 5 years: A. 98.1% B. 98.4% Fuchs et al. [54] PFS progression-free survival, OS overall survival, INRT involved-node radiotherapy, IFRT involved-field radiotherapy, n.a. not available a b NCI UK RAPID 90 Radiotherapy 80 No further treatment 90 70 60 50 40 30 20 Rate ratio, 1.57 (95% CI, 0.84-2.97) P=0.16 10 0 0 12 24 36 48 60 72 84 96 108 120 c 80 Chemotherapy only 70 60 50 40 30 20 10 0 Months since Randomization PFS Rate (%) Radiotherapy 100 Progression free survival (%) Progression free survival (%) 100 EORTC/FIL/LYSA H10 HR, 15.8 (95% CI, 3.79 to 66.07) 1 2 3 4 5 6 7 8 Time (years) GHSG HD16 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 5-year estimate (95% CI) 2x ABVD + 20 Gy IFRT 93.4% (90.4% to 96.5%) 2x ABVD 86.1% (81.4% to 90.9%) –7.3% (–13.0% to –1.6%) Difference 0 Hazard ratio (95% CI) Log-rank test 1.78 (1.02 to 3.12) P = .040 Median follow-up 47 months 12 36 24 Time (months) 48 60 Fig. 11.4 Results of the recently published trials of PET adapted trials in early favorable Hodgkin lymphoma. Shown are progression-free survival curves for the UK RAPID trial (a), EORTC/LYSA/FIL H10 favorable (b) and GHSG HD16 (c) 11 Treatment of Early Favorable Hodgkin Lymphoma b 100 90 escBEACOPP + INRT 80 70 ABVD + INRT 60 50 40 30 20 10 HR, 0.42 (95% CI, 0.23 to 0.74); P = .002 1 2 3 4 5 6 7 escBEACOPP + INRT 100 90 Overall survival (%) Progression free survival (%) a 233 8 Time (years) ABVD + INRT 80 70 60 50 40 30 20 10 HR, 0.45 (95% CI, 0.19 to 1.07); P = .062 1 2 3 4 5 6 7 8 Time (years) Fig. 11.5 Results of the EORTC/LYSA/FIL H10 trial in case of a positive FDG-PET scan after 2 ABVD among patients with both favorable and unfavorable early-stage HL. Shown are progression-free survival (a) and overall survival (b) favorable subgroup patients and two extra cycles in patients with unfavorable disease. The de- escalation arm with the substitution of radiotherapy by extra chemotherapy was closed prematurely due to futility based on 33 events. In line with the results of the RAPID trial, final results at 5-year follow-up showed that early favorable patients with a negative PET after two cycles of ABVD have an excellent outcome when treated with CMT (5-year PFS 99%). Substituting radiotherapy by a single extra course of ABVD resulted in a decrease of about 12% PFS [53]. Similar were reported from GHSG HD16 trial which was recently published. In this large trial involving 1150 patients with early favorable HL, patients with a negative PET scan after two cycles of ABVD were randomized between standard 30 Gy IFRT and no further treatment. Again omission of radiotherapy resulted in a decrease of tumor control with PFS of 93.4% at 5 years in the CMT arm versus 86.1% in the chemotherapyonly arm [54]. There were no differences in overall survival at 5 years. Taken together, these three trials demonstrated that omission of radiotherapy among patients with early-stage HL and a negative PET scan after two or three cycles of ABVD resulted in a clinically relevant decrease in PFS. Although it must be mentioned that chemotherapy-only strategies based on interim PET scanning also resulted in excellent treatment outcomes and can be seen as a treatment option for patients in whom radiotherapy is expected to result in excessive short- and/or long-term toxicity. Overall survival in all trials was not different between treatment arms meaning that almost all patients not receiving radiotherapy could successfully be salvaged. Long-term effects on overall survival of the omission of radiotherapy and the impact of salvage treatments need to be awaited. The EORTC H10 study was the only study that also investigated escalation of treatment based on a positive interim PET scan. Patients with both early favorable and early unfavorable HL and a positive interim PET scan after two cycles of ABVD subsequently received two cycles of escBEACOPP. In this joint group, escalation to escBEACOPP + INRT resulted in improved 5-year PFS of 90.6% compared to 77.4% for standard three cycles (early favorable) or four cycles (early unfavorable) of ABVD + INRT (Fig. 11.5) [53]. In conclusion, interim PET-guided treatment results in improved tumor control in patients with positive findings by escalating chemotherapy on one hand, and it gives the possibility to relatively safely omit radiotherapy where needed in patients with a complete response on ABVD chemotherapy on the other hand. W. Plattel and P. Lugtenburg 234 11.8 Recommendations and Future Directions In most parts of the world, CMT strategies including 2–3 cycles of ABVD followed by 20–30 Gy IFRT will remain standard treatment for patients with early favorable HL. Incorporation of an interim PET-guided approach with escalation to escBEACOPP in case of positive findings might further improve the already excellent treatment results. In patients at increased risk of RT-related toxicity because of age, sex, and disease localization, PET-guided treatment might aid the selection of patients in whom radiotherapy can be relatively safely omitted. Although, in such cases, omission of radiotherapy will result in a decrease of local tumor control of about 7–12%, outcomes with chemotherapy only are still excellent. Therefore, balancing the risk of RT-related toxicity to the possible decrease in local tumor control is the main challenge when planning treatment upfront. When balancing this risk, it is important to realize that data on toxicity of radiotherapy are mainly based on past radiotherapy techniques, fields, and doses, and all have been massively improved last decades. It is therefore of outmost importance to collect long-term follow-up outcomes of current treatment modalities. With this approach, PFS rates exceeding 90% and OS rates exceeding 95% can be achieved. At present, the goal in early favorable HL is to maintain the excellent efficacy while further reducing acute and late toxicity. Incorporation or replacing current chemotherapy regimens by successful new drugs in HL like brentuximab vedotin or checkpoint inhibitors might be a further improvement and a possible route to chemotherapy free treatment in HL. However, it might be difficult to improve on current excellent treatment results with only short courses of limited chemotherapy or radiotherapy. Other opportunities to improve outcome of early favorable HL are the introduction of proton beam radiotherapy, better selection of patients for certain treatments based on biomarkers, or better methods for detection of minimal residual disease (MRD) in HL. These efforts are currently being made and are further discussed in Chap. 13. References 1. Carbone PP, Kaplan HS, Musshoff K, Smithers DW, Tubiana M (1971) Report of the committee on Hodgkin’s disease staging classification. Cancer Res 31:1860–1861 2. Lister TA, Crowther D, Sutcliffe SB, Glatstein E, Canellos GP, Young RC et al (1989) Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin’s disease: Cotswolds meeting. J Clin Oncol 7:1630–1636 3. Juweid ME, Stroobants S, Hoekstra OS, Mottaghy FM, Dietlein M, Guermazi A et al (2007) Use of positron emission tomography for response assessment of lymphoma: consensus of the imaging Subcommittee of International Harmonization Project in lymphoma. J Clin Oncol 25:571–578 4. Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ et al (2007) Revised response criteria for malignant lymphoma. J Clin Oncol 25:579–586 5. El-Galaly TC, d’Amore F, Mylam KJ, de Nully Brown P, Bøgsted M, Bukh A et al (2012) Routine bone marrow biopsy has little or no therapeutic consequence for positron emission tomography/computed tomography- staged treatment naïve patients with Hodgkin lymphoma. J Clin Oncol 30:4508–4514 6. Specht L, Nissen NI (1988) Hodgkin’s disease stages I and II with infradiaphragmatic presentation: a rare and prognostically unfavourable combination. Eur J Haematol 40:396–402 7. Sasse S, Goergen H, Plütschow A, Böll B, Eichenauer DA, Fuchs M et al (2018) Outcome of patients with early-stage infradiaphragmatic Hodgkin lymphoma: a comprehensive analysis from the German Hodgkin study group. J Clin Oncol 36:2603–2611 8. Specht L (1996) Prognostic factors in Hodgkin’s disease. Semin Radiat Oncol 6:146–161 9. Tubiana M, Henry-Amar M, van der Werf-Messing B, Henry J, Abbatucci J, Burgers M et al (1985) A multivariate analysis of prognostic factors in early stage Hodgkin’s disease. Int J Radiat Oncol Biol Phys 11:23–30 10. Ferme C, Eghbali H, Meerwaldt JH, Rieux C, Bosq J, Berger F et al (2007) Chemotherapy plus involved- field radiation in early stage Hodgkin’s disease. N Engl J Med 357:1916–1927 11. Engert A, Franklin J, Eich HT, Brillant C, Sehlen S, Cartoni C et al (2007) Two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine plus extended-field radiotherapy is superior to radiotherapy alone in early favorable Hodgkin’s lymphoma: final results of the GHSG HD7 trial. J Clin Oncol 25:3495–3502 12. Cottereau AS, Versari A, Loft A, Casasnovas O, Bellei M, Ricci R et al (2018) Prognostic value of baseline metabolic tumor volume in early-stage Hodgkin lymphoma in the standard arm of the H10 trial. Blood 131:1456–1463 11 Treatment of Early Favorable Hodgkin Lymphoma 13. Hoppe RT, Coleman CN, Cox RS, Rosenberg SA, Kaplan HS (1982) The management of stage I–II Hodgkin’s disease with irradiation alone or combined modality therapy: the Stanford experience. Blood 59:455–465 14. Gospodarowicz MK, Sutcliffe SB, Clark RM, Dembo AJ, Fitzpatrick PJ, Munro AJ et al (1992) Analysis of supradiaphragmatic clinical stage I and II Hodgkin’s disease treated with radiation alone. Int J Radiat Oncol Biol Phys 22:859–865 15. Raemaekers J, Kluin-Nelemans H, Teodorovic I, Meerwaldt C, Noordijk E, Thomas J et al (2002) The achievements of the EORTC lymphoma group. European Organisation for Research and Treatment of Cancer. Eur J Cancer 38(Suppl 4):S107–S113 16. Tubiana M, Henry-Amar M, Carde P, Burgers JM, Hayat M, Van der Schueren E et al (1989) Toward comprehensive management tailored to prognostic factors of patients with clinical stages I and II in Hodgkin’s disease. The EORTC lymphoma group controlled clinical trials: 1964–1987. Blood 73:47–56 17. Tubiana M, Henry-Amar M, Hayat M, Breur K, van der Werf-Messing B, Burgers M (1979) Long-term results of the E.O.R.T.C. randomized study of irradiation and vinblastine in clinical stages I and II of Hodgkin’s disease. Eur J Cancer 15:645–657 18. Tubiana M, Hayat M, Henry-Amar M, Breur K, van der Werf MB, Burgers M (1981) Five-year results of the E.O.R.T.C. randomized study of splenectomy and spleen irradiation in clinical stages I and II of Hodgkin’s disease. Eur J Cancer 17:355–363 19. Carde P, Burgers JM, Henry-Amar M, Hayat M, Sizoo W, Van der Schueren E et al (1988) Clinical stages I and II Hodgkin’s disease: a specifically tailored therapy according to prognostic factors. J Clin Oncol 6:239–252 20. Carde P, Hagenbeek A, Hayat M, Monconduit M, Thomas J, Burgers MJ et al (1993) Clinical staging versus laparotomy and combined modality with MOPP versus ABVD in early stage Hodgkin’s disease: the H6 twin randomized trials from the European Organization for Research and Treatment of Cancer lymphoma cooperative group. J Clin Oncol 11:2258–2272 21. Noordijk EM, Carde P, Dupouy N, Hagenbeek A, Krol AD, Kluin-Nelemans JC et al (2006) Combined- modality therapy for clinical stage I or II Hodgkin’s lymphoma: long-term results of the European Organisation for Research and Treatment of Cancer H7 randomized controlled trials. J Clin Oncol 24:3128–3135 22. Duhmke E, Franklin J, Pfreundschuh M, Sehlen S, Willich N, Ruhl U et al (2001) Low-dose radiation is sufficient for the noninvolved extended-field treatment in favorable early stage Hodgkin’s disease: long- term results of a randomized trial of radiotherapy alone. J Clin Oncol 19:2905–2914 23. Specht L, Gray RG, Clarke MJ, Peto R (1998) International Hodgkin’s disease collaborative group. Influence of more extensive radiotherapy and adju- 235 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. vant chemotherapy on long-term outcome of early stage Hodgkin’s disease: a meta-analysis of 23 randomized trials involving 3,888 patients. J Clin Oncol 16:830–843 Horwich A, Specht L, Ashley S (1997) Survival analysis of patients with clinical stages I or II Hodgkin’s disease who have relapsed after initial treatment with radiotherapy alone. Eur J Cancer 33:848–853 Aleman BM, van den Belt-Dusebout AW, Klokman WJ, Van’t Veer MB, Bartelink H, van Leeuwen FE (2003) Long-term cause-specific mortality of patients treated for Hodgkin’s disease. J Clin Oncol 21:3431–3439 Ng AK, Bernardo MP, Weller E, Backstrand KH, Silver B, Marcus KC et al (2002) Long-term survival and competing causes of death in patients with early stage Hodgkin’s disease treated at age 50 or younger. J Clin Oncol 20:2101–2108 Favier O, Heutte N, Stamatoullas-Bastard A, Carde P, Van’t Veer MB, Aleman BM et al (2009) Survival after HL: causes of death and excess mortality in patients treated in 8 consecutive trials. Cancer 115: 1680–1691 Canellos GP, Anderson JR, Propert KJ, Nissen N, Cooper MR, Henderson ES et al (1992) Chemotherapy of advanced Hodgkin’s disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med 327:1478–1484 Press OW, LeBlanc M, Lichter AS, Grogan TM, Unger JM, Wasserman TH et al (2001) Phase III randomized intergroup trial of subtotal lymphoid irradiation versus doxorubicin, vinblastine, and subtotal lymphoid irradiation for stage IA to IIA Hodgkin’s disease. J Clin Oncol 19:4238–4244 Horning SJ, Hoppe RT, Mason J, Brown BW, Hancock SL, Baer D et al (1997) Stanford-Kaiser Permanente G1 study for clinical stage I to IIA Hodgkin’s disease: subtotal lymphoid irradiation versus vinblastine, methotrexate, and bleomycin chemotherapy and regional irradiation. J Clin Oncol 15:1736–1744 Zittoun R, Audebert A, Hoerni B, Bernadou A, Krulik M, Rojouan J et al (1985) Extended versus involved fields irradiation combined with MOPP chemotherapy in early clinical stages of Hodgkin’s disease. J Clin Oncol 3:207–214 Noordijk EM, Carde P, Dupouy N, Hagenbeek A, Krol AD, Kluin-Nelemans JC et al (2006) Combined- modality therapy for clinical stage I or II Hodgkin’s lymphoma: long-term results of the European Organisation for Research and Treatment of Cancer H7 randomized controlled trials. J Clin Oncol 24:3128–3135 Engert A, Plütschow A, Eich HT, Lohri A, Dörken B, Borchmann P et al (2010) Reduced treatment intensity in patients with early-stage Hodgkin’s lymphoma. N Engl J Med 363:640–652 Behringer K, Görgen H, Hitz F, Zijlstra JM, Greil R, Markova J et al (2015) Omission of dacarbazine or bleomycin, or both, from the ABVD regimen in treatment of early-stage favourable Hodgkin’s lymphoma W. Plattel and P. Lugtenburg 236 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. (GHSG HD13): an open-label, randomised, non-inferiority trial. Lancet 11;385:1418–1427 Advani RH, Hoppe RT, Baer D, Mason J, Warnke R, Allen J et al (2013) Efficacy of abbreviated Stanford V chemotherapy and involved-field radiotherapy in early-stage Hodgkin lymphoma: mature results of the G4 trial. Ann Oncol 24:1044–1048 Bonadonna G, Bonfante V, Viviani S, Di Russo A, Villani F, Valagussa P (2004) ABVD plus subtotal nodal versus involved-field radiotherapy in early stage Hodgkin’s disease: long-term results. J Clin Oncol 22:2835–2841 Thomas J, Fermé C, Noordijk EM, Morschhauser F, Girinsky T, Gaillard I et al (2018) Comparison of 36 Gy, 20 Gy, or no radiation therapy after 6 cycles of EBVP chemotherapy and complete remission in early- stage Hodgkin lymphoma without risk factors: results of the EORT-GELA H9-F intergroup randomized trial. Int J Radiat Oncol Biol Phys 100:1133–1145 Engert A, Schiller P, Josting A, Herrmann R, Koch P, Sieber M et al (2003) Involved-field radiotherapy is equally effective and less toxic compared with extended-field radiotherapy after four cycles of chemotherapy in patients with early stage unfavorable Hodgkin’s lymphoma: results of the HD8 trial of the German Hodgkin’s lymphoma study group. J Clin Oncol 21:3601–3608 Girinsky T, van der Maazen R, Specht L, Aleman B, Poortmans P, Lievens Y et al (2006) Involved-node radiotherapy (INRT) in patients with early HL: concepts and guidelines. Radiother Oncol 79:270–277 Shahidi M, Kamangari N, Ashley S, Cunningham D, Horwich A (2006) Site of relapse after chemotherapy alone for stage I and II Hodgkin’s disease. Radiother Oncol 78:1–5 Girinsky T, Specht L, Ghalibafian M, Edeline V, Bonniaud G, Van Der Maazen R et al (2008) The conundrum of HL nodes: to be or not to be included in the involved node radiation fields. The EORTC- GELA lymphoma group guidelines. Radiother Oncol 88:202–210 Campbell BA, Voss N, Pickles T, Morris J, Gascoyne RD, Savage KJ et al (2008) Involved-nodal radiation therapy as a component of combination therapy for limited-stage Hodgkin’s lymphoma: a question of field size. J Clin Oncol 26:5170–5174 Longo DL, Glatstein E, Duffey PL, Young RC, Hubbard SM, Urba WJ et al (1991) Radiation therapy versus combination chemotherapy in the treatment of early stage Hodgkin’s disease: seven-year results of a prospective randomized trial. J Clin Oncol 9:906–917 Biti GP, Cimino G, Cartoni C, Magrini SM, Anselmo AP, Enrici RM et al (1992) Extended-field radiotherapy is superior to MOPP chemotherapy for the treat- 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. ment of pathologic stage I–IIA Hodgkin’s disease: eight-year update of an Italian prospective randomized study. J Clin Oncol 10:378–382 Meyer RM, Gospodarowicz MK, Connors JM, Pearcey RG, Wells WA, Winter JN et al (2012) ABVD alone versus radiation-based therapy in limited-stage Hodgkin’s lymphoma. N Engl J Med 366:399–408 Straus DJ, Portlock CS, Qin J, Myers J, Zelenetz AD, Moskowitz C et al (2004) Results of a prospective randomized clinical trial of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by radiation therapy (RT) versus ABVD alone for stages I, II, and IIIA nonbulky Hodgkin disease. Blood 104:3483–3489 Gallamini A, Hutchings M, Rigacci L, Specht L, Merli F, Hansen M et al (2007) Early interim 2-[18F]fluoro- 2- deoxy-D-glucose positron emission tomography is prognostically superior to international prognostic score in advanced-stage Hodgkin’s lymphoma: a report from a joint Italian-Danish study. J Clin Oncol 25:3746–3752 Hutchings M, Mikhaeel NG, Fields PA, Nunan T, Timothy AR (2005) Prognostic value of interim FDG- PET after two or three cycles of chemotherapy in HL. Ann Oncol 16:1160–1168 Hutchings M, Loft A, Hansen M, Pedersen LM, Buhl T, Jurlander J et al (2006) FDG-PET after two cycles of chemotherapy predicts treatment failure and progression-free survival in HL. Blood 107:52–59 Oki Y, Chuang H, Chasen B, Jessop A, Pan T, Fanale M et al (2014) The prognostic value of interim positron emission tomography scan in patients with classical Hodgkin lymphoma. Br J Haematol 165:112–116 Gallamini A, Barrington SF, Biggi A, Chauvie S, Kostakoglu L, Gregianin M (2014) The predictive role of interim positron emission tomography for Hodgkin lymphoma treatment outcome is confirmed using the interpretation criteria of the Deauville five- point scale. Haematologica 99:1107–1113 Radford J, Illidge T, Counsell N, Hancock B, Pettengell R, Johnson P (2015) Results of a trial of PET-directed therapy for early-stage Hodgkin’s lymphoma. N Engl J Med 372:1598–1607 André MPE, Girinsky T, Federico M, Reman O, Fortpied C, Gotti M (2017) Early positron emission tomography response-adapted treatment in stage I and II Hodgkin lymphoma: final results of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol 35:1786–1794 Fuchs M, Goergen H, Kobe C, Kuhnert G, Lohri A, Greil R et al (2019) Positron emission tomographyguided treatment in early-stage favorable Hodgkin lymphoma: final results of the international, randomized phase III HD16 trial by the German Hodgkin Study Group. J Clin Oncol 37:2835–2845 Treatment of Early Unfavorable Hodgkin Lymphoma 12 Marc P. E. André and Andreas Engert Contents 12.1 12.1.1 12.1.2 Prognostic Factors Definition New Prognostic Factors 237 237 240 12.2 Long-Term Side Effects 240 12.3 12.3.1 12.3.2 12.3.3 Non-PET-Adapted Treatment Strategies Fields and Dose of Radiotherapy Chemotherapy Chemotherapy Alone 241 241 241 242 12.4 12.4.1 12.4.2 12.4.2.1 12.4.2.2 12.4.2.3 12.4.2.4 PET-Adapted Treatment Strategies Interim PET Clinical Trials Rapid Study H10 Study Other Studies Management of iPET-Positive Patients 242 242 243 243 243 244 244 12.5 ESMO and NCCN Recommendations 244 12.6 12.6.1 12.6.2 New Drugs Brentuximab Vedotin Checkpoint Inhibitors 245 245 245 12.7 Conclusions and Future Strategies 246 References M. P. E. André (*) Department of Hematology, Université Catholique de Louvain, CHU UcL Namur, Yvoir, Belgium e-mail: marc.andre@uclouvain.be A. Engert Department of Internal Medicine I, German Hodgkin Study Group (GHSG), University Hospital of Cologne, Cologne, Germany e-mail: a.engert@uni-koeln.de 246 12.1 Prognostic Factors 12.1.1 Definition The Ann Arbor staging system with the 1989 Cotswolds modifications is still being used worldwide in patients with Hodgkin lymphoma (HL) [1]. Modern staging procedures recommend © Springer Nature Switzerland AG 2020 A. Engert, A. Younes (eds.), Hodgkin Lymphoma, Hematologic Malignancies, https://doi.org/10.1007/978-3-030-32482-7_12 237 M. P. E. André and A. Engert 238 the routine use of [18F] fluoro-2-deoxy-D-glucose positron emission tomography-CT scanning (PET-CT) at diagnosis [2]. With the introduction of PET-CT scanning at diagnosis, up to 30% of patients will be upstaged mainly from early to advanced stages. In addition, the extent of radiation fields in CS I/II disease can be influenced by identifying additional lesions by PET-CT scanning [2, 3]. Interestingly, when a PET-CT is performed for initial staging, a bone marrow biopsy is no longer required [4, 5]. In the study by El-Galaly et al. [5], 18% of patients showed focal skeletal lesions on PET-CT, but only 6% had positive bone marrow biopsies. None of the patients would have been allocated to other treatments based on bone marrow biopsy results. Patients with early-stage disease rarely have bone marrow involvement in the absence of a suggestive PET finding, confirming that, if a PET-CT is performed, a bone marrow aspirate/biopsy is no longer required for the routine evaluation. Even in stage I/II, the extent of disease varies substantially requiring a risk-adapted treatment. In many early-stage patients, mediastinal bulky disease is present, which has been demonstrated as prognostically unfavorable. Other poor prognostic clinical factors include higher age, increased number of involved nodes, and elevated erythrocyte sedimentation rate (ESR), accompanied by B symptoms. Though slight differences in definition exist between major cooperative groups, clinical stage I/II HL patients in Europe are generally divided into an early favorable and an early unfavorable (intermediate) subgroup. Patients in North America presenting with adverse factors (mainly the presence of bulky disease) are treated like those having stage III–IV disease; thus, these patients are not included in clinical trials for stage I/II disease. The factors used by the European Organization for Research and Treatment of Cancer (EORTC) Lymphoma Group/Lymphoma Study Association (LYSA), the German Hodgkin Study Group (GHSG), the National Cancer Institute of Canada (NCIC), and the Eastern Cooperative Oncology Group (ECOG) are shown in Table 12.1. These risk factors and the resulting prognostic groups were originally defined in the context of treatment with extended-field radiotherapy (RT). In a combined modality setting, the differences in prognosis between favorable and unfavorable disease are likely to be smaller. In more recent series, the treatment was mainly tailored according to the prognostic group. Thus, one would have anticipated that these prognostic factors today have less independent prognostic significance. Klimm et al. analyzed the impact of the three different staging and prognostic subgroup definitions on the outcome of 1173 early-stage patients treated homogeneously in the HD10 and HD11 trials of the GHSG [6]. Figure 12.1 shows the PFS of these patients related to the GHSG, EORTC/LYSA, and NCCN prognostic risk factor score, respectively: all three staging systems identified the unfavorable risk group. Especially tumorspecific risk factors rather than patient-specific risk factors such as mediastinal bulk and high tumor activity were predictive for poor outcome. Table 12.1 Risk factors according to cooperative treatment groups Risk factors (RF) Stages Favorable Unfavorable or intermediate EORTC/LYSA A: Mediastinal mass GHSG A: Mediastinal mass B: Age ≥ 50 years C: ESR ≥ 50 or ESR ≥ 30 with B symptoms D: ≥ 4 nodal areas B: Extranodal disease C: ESR ≥ 50 NCIC/ECOG A: Histology other than LP/NS B: age > 40 C: ESR > 50 D: ≥ 3 nodal areas D: ≥ 3 sites I–II without RF I–II with ≥1 RF and IIB with C/D without AB I–II without RF I–II with ≥1 RF I–II without RF I–II with ≥1 RF EORTC European Organization for Research and Treatment of Cancer, LYSA Lymphoma Study Association, GHSG German Hodgkin Study Group, NCIC National Cancer Institute of Canada, ECOG Eastern Cooperative Oncology group, ESR erythrocyte sedimentation rate, LP lymphocyte predominance, NS nodular sclerosis 12 Treatment of Early Unfavorable Hodgkin Lymphoma GHSG 239 1.0 0.9 0.8 0.7 5 year estimate [95 %-CI]: 95.8 % [94.0 % to 97.6 %] Favorable 86.4 % [83.7 % to 89.1 %] Unfavorable PFS 0.6 0.5 0.3 p = <.001 0.2 0.1 Favorable 0.0 Pts. at risk favorable unfavorable EORTC –9.4 % [–12.7 % to –6.2 %] 2.61 [1.74 to 3.91] difference Hazard ratio 0.4 0 12 24 525 648 504 614 486 568 36 48 60 Time [months] 463 437 390 543 513 475 Unfavorable 72 84 96 302 375 209 247 123 141 72 84 96 282 348 195 232 118 126 72 84 96 291 375 205 245 125 136 1.0 PFS 0.9 0.8 5 year estimate [95 %-CI]: 0.7 Favorable Unfavorable 94.2 % [92.1 % to 96.4 %] 87.6 % [84.8 % to 90.3%] difference Hazard ratio –6.7 % [–10.2 % to –3.2 % ] 2.10 [1.41 to 3.13] 0.6 0.5 0.4 0.3 p = <.001 0.2 0.1 Favorable 0.0 Pts. at risk favorable unfavorable NCCN 0 12 24 496 589 473 560 455 517 36 48 60 Time [months] 433 406 355 495 470 444 Unfavorable 1.0 0.9 0.8 5 year estimate [95 %-CI]: PFS 0.7 0.6 0.5 0.4 Favorable Unfavorable 95.3 % [93.3 % to 97.2 %] 86.7 % [84.0 % to 89.3%] difference Hazard ratio –8.6 % [–11.9 % to –5.3 % ] 2.14 [1.45 to 3.16] 0.3 p = <.001 0.2 0.1 Favorable 0.0 Pts. at risk favorable unfavorable 0 12 24 506 645 483 616 467 569 36 48 60 Time [months] 444 416 371 544 516 478 Fig. 12.1 Estimated progression-free survival using staging definitions of the German Hodgkin Study Group, the European Organization for Research and Treatment of Unfavorable Cancer (EORTC), or National Comprehensive Cancer Network (NCCN) [6] M. P. E. André and A. Engert 240 Table 12.2 Multivariate analysis testing total metabolic tumor volume (TMTV), with interim PET response after two cycles (iPET2) and individual baseline factors, EORTC, GHSG, NCCN staging systems TMTV tested with: A. Individual factors TMTV > 147 cm3 IPET 2 B symptoms ≥ 4 involved sites M/T ≥ 0.35 B.EORTC TMTV > 147 cm3 IPET2 Unfavorable EORTC C.GHSG TMTV > 147 cm3 IPET2 Unfavorable GHSG D.NCCN TMTV > 147 cm3 IPET2 Unfavorable NCCN PFSa HR 95% CI P PFS (final model) HR 95% CI P 3.9 11.0 2.1 2.0 0.8 1.6–9.5 4.8–25.1 0.9–4.8 0.8–5.2 0.3–2.0 0.0032 <0.0001 0.076 0.16 0.65 4.4 10.9 2.0–9.5 4.9–24.4 0.0002 <0.0001 3.5 9.2 3.2 1.6–7.8 4.1–20.6 0.9–11.1 0.0016 <0.0001 0.067 4.4 10.9 2.0–9.5 4.9–24.4 0.0002 <0.0001 4.1 10.6 1.3 1.8–9.3 4.7–23.9 0.4–4.0 0.0006 <0.0001 0.69 4.4 10.9 2.0–9.5 4.9–24.4 0.0002 <0.0001 3.7 10.2 1.8 1.7–8.4 4.5–22.8 0.6–5.7 0.00014 <0.0001 0.30 4.4 10.9 2.0–9.5 4.9–24.4 0.0002 <0.0001 All variables integrated in the Cox model; final model: with significant factors after performing the backward stepwise Cox model (Adapted from Cottereau, Blood 2018 with permission) a In terms of overall survival, the scores reflected the unfavorable risk profile as well. These data underline the continued need for identifying a poor-risk group within the group of stage I/II disease though new risk factors with a higher specificity might be useful. 12.1.2 New Prognostic Factors Several different prognostic factors adopted so far are surrogates of the tumor burden. Specht et al. [7] were the first to demonstrate the strong prognostic impact of tumor burden attempting to estimate tumor volume. This was based on the categorization of lesion size by physical examination as well as mediastinal and hilar involvement (chest X-rays) as well as adding grades of all involved sites. The superiority of tumor burden over other prognostic factors was further confirmed by Gobbi et al. [8]. More recently, PET-CT scanning has been used to define the functionally active tumor volume using total metabolic tumor volume (TMTV). Cottereau et al. conducted an analysis on 294 early-stage HL including interim PET and TMTV in the different prognostic models (EORTC/LYSA, GHSG and NCC) [9]. In this analysis, only TMTV and interim PET remained significant (Table 12.2). Although PET-CT is a tool that allows to refine prognosis and treatment strategies if there is a certain degree of inaccuracy in its application. An area of growing interest is combing PET-CT and biomarkers such as circulating tumor-free DNA. Spina et al. recently demonstrated that this biomarker could identify residual disease during treatment of disease after two courses of treatment [10]. Incorporation of both, PET-CT and cell-free tumor DNA, in our decision algorithm will possibly profoundly modify the way we use prognostic factors in the future. 12.2 Long-Term Side Effects The present management of early-stage HL aims at curing the disease with a specific attention to the reduction of late effects. The most severe late effect due to the treatment of HL is secondary cancer. In a recent large study [11] with a median follow-up of 19.1 years, the standardized incidence 12 Treatment of Early Unfavorable Hodgkin Lymphoma ratio was 4.6 (95% confidence interval (CI), 4.3– 4.9) in the study cohort when compared with the general population. The risk was still elevated 35 years or more after treatment (SIR, 3.9; 95% CI, 2.8–5.4), and the cumulative incidence of a second cancer in the study cohort at 40 years was 48.5% (95% CI, 45.4–51.5). Unfortunately, the cumulative incidence of second solid cancers did not differ between study periods (1965–1976, 1977– 1988, or 1989–2000) (P = 0.71 for heterogeneity), suggesting that the efforts made to reduce the burden of treatment did not translate into a reduction of second cancers. However, the impact of treatment modifications in the last 20 years is not well known. Also, as the risk is better known, it might be suggested that well-conducted cancer screening programs could also reduce the severity of late malignancies. However, in the study of Baxstrom et al. [12], many women did not get the appropriate dual screening for breast cancer despite their increased risk, with only 36.6% of the study sample receiving dual screening. Proper screening allows detection of secondary breast cancer at earlier stages where treatment can be local, but this study raised the issue of compliance of this population to cancer screening programs. Finally, cancer screening is not yet possible for thyroid, lung, and soft tissue cancers. Cardiovascular and valvular diseases represent another important late effect occurring in patients receiving mediastinal radiotherapy [13, 14]. The reduction in dose and volume of radiotherapy led to a reduction in these complications. Nevertheless, radiotherapy may still result in substantial incidental cardiac exposure if the disease affects the mediastinum. 12.3 Non-PET-Adapted Treatment Strategies 12.3.1 Fields and Dose of Radiotherapy The use of large radiation fields was abandoned after both, the GHSG HD8 trial [15] and the H8U trial conducted by the EORTC/LYSA [16]. In HD8, long-term noninferiority of involved-field radiotherapy (IF-RT) was compared with extended-field 241 RT. With regard to treatment-associated long-term toxicity, a non-significant trend towards less secondary neoplasia was observed with IF-RT in the most recent follow-up analysis (15-year cumulative, 14% vs. 17%; p = 0.3) [17]. This trend was more pronounced when examining only the incidence of acute myeloid leukemia or myelodysplastic syndromes (2.4% vs. 0.8%; p = 0.1), but not in nonHodgkin lymphoma (2.6% vs. 2.9%; p = 1.0). In solid second neoplasia, the trend became more pronounced with longer follow-up but did not meet statistical significance (12% vs. 10.4%; p = 0.7). Due to the long latency period of second solid neoplasia, prolonged follow-up is crucial to finally assess the risk of secondary malignancies with more limited RT fields. In the H8U trial, 42 of 766 (5%) patients relapsed who had a confirmed or unconfirmed complete remission after radiotherapy: 15 of 253 patients (6%) in the group received six cycles of MOPP-ABV plus IF-RT, 14 of 259 patients (5%) in the group received four cycles of MOPP-ABV plus IF-RT, and 13 of 254 patients (5%) in the group received MOPP-ABV plus subtotal nodal RT [16]. There were no significant differences in the 5-year event-free survival estimates among the three groups. The GHSG used a two-by-two factorial design in the HD11 trial aimed at comparing unfavorable early-stage HL using two different chemotherapy regimen: 4xABVD vs. 4xBEACOPPbaseline (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristin, procarbazin, prednisone) as well as 30 Gy IF-RT vs. 20 Gy [18]. Concerning RT, the 20 Gy arm was inferior to 30 Gy when ABVD was used, but when BEACOPP was used, this difference disappeared and 20 Gy was equivalent to 30 Gy. Taken together, 4xABVD and 30 Gy IF-RT were considered as standard of care for early unfavorable HL. 12.3.2 Chemotherapy Besides the objective of reducing long-term toxicity with dose and field reductions, investigators aimed at improving disease control further by modifying chemotherapy schemes. M. P. E. André and A. Engert 242 The GHSG HD11 study was based on a two- by-two factorial design with the aim of comparing patients between two different regimen in unfavorable early-stage HL: 4xABVD vs. 4xBEACOPPbaseline (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristin, procarbazin, prednisone) and 30 Gy IF-RT vs. 20 Gy [18]. No improvement was demonstrated using four cycles of BEACOPPbaseline compared with four cycles of ABVD. Similarly, the EORTC/LYSA H9U [19] study compared 6 cycles of ABVD and 30 Gy IF-RT (standard arm) with 4xABVD and 30 Gy IF-RT and 4xBEACOPPbaseline followed by 30 Gy IF-RT. Results in the 4xABVD and IF-RT (5-year EFS, 85.9%) and the 4xBEACOPPbaseline and IF-RT (5-year EFS, 88.8%) were not inferior to 6xABVD and IF-RT (5-year EFS, 89.9%) differences of 4.0% (90% CI, −0.7% to 8.8%) and of 1.1% (90% CI, −3.5% to 5.6%), respectively. The 5-year OS estimates were 94%, 93%, and 93%, respectively. Because four cycles of BEACOPPbaseline were more toxic but equally efficient than four cycles of ABVD, it was not considered as a new standard. In their HD14 follow-up trial, the GHSG compared four cycles of ABVD and 30 Gy IF-RT with two BEACOPPesc plus two ABVD and 30 Gy IF-RT. With a total of 1528 patients included, a significant PFS advantage for « 2+2 » compared with 4xABVD was detected with a 5-year PFS difference of 6.2% (95.4% vs. 89.1%; HR, 0.45; 95% CI, 0.3–0.69) [20]. The « 2+2 » approach, however, is associated with more hematologic toxicity, but no difference in long- term toxicity or OS has been documented so far. A longer follow-up will be needed to assess potential risks and long-term benefits with intensive upfront therapy in patients with early-stage unfavorable disease. 12.3.3 Chemotherapy Alone Based on randomized trials performed in advanced Hodgkin lymphoma patients and the risk of late complications after radiotherapy, the question arose whether RT can also be omitted in unfavorable early stages. A number of trials conducted had important limitations: some trials included pediatric patients, all stages of disease used divergent definitions of unfavorable prognostic features, or there was a lack of statistical power to detect clinically relevant differences in PFS between RT and no-RT arms. The NCIC/ ECOG study on early stages had 12-year overall survival as primary endpoint; patients with bulky disease were excluded from entry [21]. This study showed a significant 11% survival benefit for treatment with ABVD alone as compared to ABVD+STNI, notwithstanding a significant 8% advantage in PFS for those who received combined modality treatment. The remarkable conversion of an inferior PFS to a superior long-term OS for the ABVD-alone treatment arm was mainly due to an excess of late toxic deaths in the combined modality treatment (CMT): 23 vs. 11 in the former. These deaths were mainly due to second cancers and intercurrent disease. Admittedly, STNI has become outdated, but the results corroborate the difficulties in interpreting different treatment approaches with divergent short-term (control of disease) and long-term (toxicity) effects. 12.4 PET-Adapted Treatment Strategies 12.4.1 Interim PET In the publication of Gallamini et al., 260 newly diagnosed HL patients were consecutively enrolled in order to evaluate the prognostic role of an interim PET-CT (iPET). Most of the patients were advanced HL, and the study showed that iPET overshadows the prognostic value of the International Prognostic Score and emerges as the single most important tool for planning of risk-adapted treatment in advanced HL [22]. A similar evaluation conducted in 257 stage I to IIA patients treated with chemotherapy plus radiation therapy led to similar conclusions showing that iPET was a strong prognostic factor for both, progression free and OS [23]. The standardization of iPET is critical for the appropriate incorporation of this imaging modal- 12 Treatment of Early Unfavorable Hodgkin Lymphoma ity into routine clinical practice. For this purpose, successive international interpretation criteria have been proposed and are regularly updated according to improvement of diagnosis, treatment, and follow-up modalities. The current recommendation is to use the 2014 Lugano Classification for response assessment but also for staging of HL [24]. The Deauville 5-point scale criteria (D5PS) allow for more accurate measurement of response by using a categorical scoring system designed for the visual interpretation of PET-CT. This score is now well validated and reproducible [25]. However, it should be emphasized that the definition of PET-CT negativity to escalate or deescalate therapy has been highly variable between studies changing with the evolution of interpretation criteria. The actual recommendation is to classify PET-CT with a D5SP <4 as negative and D5SP >3 as positive. This categorization is also in agreement with the PET-CT results of the phase III H10 trial in early-stage HL recently reanalyzed using the D5PS criteria showing that patients with an interim PET-CT having a D5SP <4 have a prognosis similar to those with D5PS of 1 or 2 [9]. Subsequently, several trials were launched with the aim to evaluate early treatment adaptation according to iPET results after 2 or 3 cycles of ABVD. 12.4.2 Clinical Trials 12.4.2.1 Rapid Study In the UK RAPID trial, 602 patients with newly diagnosed stage IA or stage IIA HL received 3 cycles of ABVD and then underwent iPET [26]. RAPID included both, favorable (2/3) and unfavorable (1/3) early-stage HL in the same trial according to GHSG or EORTC/LYSA risk classification. Patients with negative iPET (Deauville score of 1 or 2) were randomly assigned to receive IF-RT or no further treatment; patients with positive iPET (Deauville score 3–5) received a fourth cycle of ABVD and RT. The 3-year progression-free survival rate was 94.6% (95% CI, 91.5–97.7) in the RT group and 90.8% (95% CI, 243 86.9–94.8) in the group receiving no further therapy, with an absolute risk difference of −3.8 percentage points (95% CI, −8.8–1.3). As the upper confidence interval limit exceeded the predefined non-inferiority margin of 7%, the study did not show non-inferiority of the strategy of no further treatment. Nevertheless, patients in this study with early-stage HL and negative iPET findings after three cycles of ABVD had a very good prognosis either with or without consolidation radiotherapy. The impact on overall survival and late effects needs additional follow-up. 12.4.2.2 H10 Study Actually, the only published study to evaluate an iPET approach in the specific group of unfavorable patients is H10 [27]. Unfavorable patients were defined as age ≥50 years, large mediastinal mass (M/T ratio >0.35), elevated erythrocyte sedimentation rate (with B symptoms, ≥30 mm/h; without B symptoms, ≥50 mm/h), and >3 nodal areas. Patients with a negative iPET were randomized between 4xABVD followed by IN-RT (n = 292) or 6 cycles of ABVD (n = 302). After a median follow-up of 5.1 years, a total of 54 PFS events have occurred: 16 patients experienced relapsed disease and 6 died from causes not related to HL in the ABVD + IN-RT arm. In contrast, 30 patients experienced relapse and 2 died from causes not related to HL in the ABVD-only arm. Intention-to-treat 5-year PFS rates were 92.1% (95% CI, 88.0–94.8) and 89.6% (95% CI, 85.5– 92.6) in the ABVD + IN-RT and ABVD- only arms, respectively, with HR 1.45 (95% CI, 0.8– 2.5) favoring ABVD + IN-RT. Non-inferiority could not be demonstrated as the upper bound of the 95% CI for the estimated HR (2.50) exceeded the prespecified non-inferiority margin (2.10). However, the difference for the 5-year PFS was only 2.5% (95% CI: −6.6% −0.5%) fitting in the range of the 10% prespecified non-inferiority margin. Therefore, in this group of unfavorable patients, the benefit of combined modality treatment seems to be less clinically relevant than in the favorable group. In the 594 unfavorable patients, 30/302 developed relapse after chemotherapy alone vs. 16/292 after CMT. Relapses after chemotherapy alone M. P. E. André and A. Engert 244 Management of iPETPositive Patients In the RAPID [26] and HD17 trial, patients with a positive iPET received the standard arm of treatment. So far, only the data from RAPID are published. Among the 571 patients enrolled in the study having an iPET after 3 ABVD, 145 were iPET positive (D5PS 3–5). So far, 127 of the 145 12.4.2.3 Other Studies patients (87.6%) in the group with positive PET In the 50604 phase 2 trial, patients with non-bulky findings were alive without disease progression. stage I/II disease with a negative iPET after There had been 18 events in this group: 10 events 2xABVD (135 of 149 patients, Deauville score of disease progression (6.9% of the patients), 5 (DS), 1–3) were treated with an additional deaths with disease progression (3.4% of the 2xABVD without consolidative RT, whereas patients), and 3 deaths without disease progrespatients with a positive iPET (14 of 149 patients) sion (2.1% of the patients). A total of 8 of the 14 received 2xBEACOPPesc and 30 Gy patients (57.1%) in this group who required secIF-RT. Estimated 3 years PFS rates of 91% and ond-line treatment received high-dose chemother66%, respectively, for the iPET-negative and PET- apy followed by autologous transplant. positive cohorts were reported (p = 0.011), HR In the H10 study, iPET-positive patients from 3.84 (95% CI, 1.50–9.84) [28]. These data sug- both favorable and unfavorable groups were gest that four cycles of ABVD result in durable included together, because of their presumed remissions for the majority of patients with early- shared poor prognosis, in a randomized trial comstage non-bulky HL and negative iPET. paring 3-4xABVD and RT vs. 2xABVD + 2xBEAThe GHSG HD17 study evaluating iPET- COPPesc and IN-RT. In the overall iPET-positive adapted treatment in unfavorable patients has group (n = 361) and a median follow-up of 4.5 completed recruitment, but results are pending. years, a total of 57 events for PFS occurred: 41 (36 The trial compares 2xBEACOPPesc + 2xABVD, relapses and 5 deaths not related to HL) in the and RT vs. 2xBEACOPPesc + 2xABVD in iPET- ABVD + IN-RT arm and 16 (13 relapses and 3 negative patients. Major difference comparing deaths not related to HL) in the BEACOPPesc + the different studies are reported in (Table 12.3). IN-RT arm. Intent-to-treat 5-year PFS rates were 77.4% (95% CI, 70.4–82.9) and 90.6% (95% CI, 84.7–94.3) in the ABVD + INRT and Table 12.3 Comparison of RAPID, H10, and HD17 BEACOPPesc + IN-RT arms, respectively, with an trials HR of 0.42 (95% CI, 0.23–0.74; P = 0.002) in favor H10 RAPID HD17 of BEACOPPesc + IN-RT. The 5-year OS rates PET baseline 95% 0% 0% were 89.3% vs. 96.0% for ABVD + IN-RT and Interim PET 2xABVD 3xABVD 2xABVD BEACOPPesc + IN-RT, respectively, with an HR PET review 75% 100% 100% of 0.45 (95% CI, 0.19–1.07; P = 0.062) (Fig. 12.2). Noninferiority 10% 7% occurred <2 years in 27/30 patients and in 3 patients after 2 years. Relapses after CMT occurred <2 years in 8/16 patients, and in 8 patients after 2 years. Relapses after chemotherapy occurred mostly in initially involved areas in 26/30. After CMT, relapses in involved areas were observed in 9/16 patients (Table 12.3). margin Stage I–IIB (bulky) Radiotherapy IN RT 30Gy PET interpretation I–IIA IF RT 30Gy 5-point International Harmonization scale Project [38] I–IIB (bulky without RF) IF RT 30Gy 5-point Deauville score 12.4.2.4 12.5 ESMO and NCCN Recommendations The recently published ESMO guidelines recommend for intermediate stage: 4xABVD or 2xBEACOPPesc + 2xABVD and 30 Gy IS-RT or 2xABVD and an iPET, if the iPET is negative: 2 12 Treatment of Early Unfavorable Hodgkin Lymphoma 245 b 100 90 80 70 60 50 40 30 20 10 Overall Survival (%) Progression -Free Survival (%) a HR, 0.42 (95% Cl, 0.23 to 0.74); P = .002 0 1 2 3 4 5 6 7 100 90 80 70 60 50 40 30 20 10 HR, 0.45 (95% Cl, 0.19 to 1.07); P = .062 0 8 1 2 O 41 n 3 4 5 6 7 8 Time (years) Time (years) No. at risk O 192 167 156 147 105 57 21 0 ABVD + INRT 16 169 157 152 141 95 61 14 1 BEACOPPesc + INRT n No. at risk 18 192 189 181 167 119 65 24 0 ABVD + INRT 7 169 166 161 149 101 63 15 1 BEACOPPesc + INRT Fig. 12.2 PFS (a) and OS (b) of patients iPET positive patients included in the H10 trial. After 2xABVD patients were randomized between 2xABVD and 30 Gy INRT vs. 2xBEACOPPesc and 30 Gy INRT. Reprinted from André et al. with permission additional ABVD and 30 Gy IS-RT and if iPET is positive: 2 additional BEACOPPesc and 30 Gy IS-RT [4]. The 2017 NCCN guidelines recommend a PET-guided approach. For intermediate or unfavorable disease and bulky mediastinum, several options are discussed including the HD14, H10 approaches but also Stanford V [29]. a randomized multicenter, phase II trial in order to improve the PET response rate after 2 cycles with BV-AVD for previously untreated, early-stage unfavorable HL [31]. In total, 170 patients were included, 113 were randomized in the BV-AVD arm and 57 in the ABVD arm. After 2 cycles of treatment, 93/113 patients (82.3%, 95% CI 75.3– 88.0) and 43/57 (75.4%, 95% CI 64.3–84.5) achieved a negative PET (Deauville score 1–3) based on central review in the experimental and standard arms, respectively. With the lower bound of the 90% confidence interval superior to 75% in the experimental arm, the primary objective can be considered to be met. An increased toxicity with BV-AVD regimen compared to ABVD was observed with a higher rate of grade 3–4 AEs and SAEs during treatment. In another trial, Kumar et al. treated 29 early-stage unfavorable patients with 4 cycles of BV-AVD followed by 20 Gy involved-site radiotherapy, and 90% of patients achieved a negative PET after two cycles [32]. 12.6 New Drugs 12.6.1 Brentuximab Vedotin Brentuximab vedotin (BV) is an antibody–drug conjugate composed of a CD30-targeted chimeric monoclonal antibody covalently linked to the microtubule disrupting agent monomethyl auristatin E via a protease-cleavable linker. In a phase 2 single-arm study, patients with relapsed or refractory HL treated with BV after failure of high-dose chemotherapy and post-autologous stem-cell transplant, 76 (75%) of 102 patients achieved an objective response, and 35 patients (34%) achieved complete remission. Adverse events were manageable with dose reduction or delay. BV was also tested in combination with AVD chemotherapy (BV-AVD) demonstrating promising efficacy with a favorable safety profile in a phase I trial for treatment-naive patients [30]. Based on these results, Fornecker et al. conducted 12.6.2 Checkpoint Inhibitors Nivolumab and Pembrolizumab are immune checkpoint inhibitors targeting the programmed death-1 receptor [33, 34]. These checkpoint inhibitors augment T-cell activation and restore antitumor T-cell function. In the phase 2 CheckMate 205 study, nivolumab demonstrated M. P. E. André and A. Engert 246 frequent (65–73%) and durable objective responses across 3 cohorts of patients with relapsed/refractory HL after failure of autologous hematopoietic cell transplantation. Cohort D of CheckMate 205 enrolled untreated patients with advanced-stage newly diagnosed HL (stage III, IV, or II with B symptoms and extranodal or bulky disease). Nivolumab monotherapy followed by N-AVD combination therapy was well- tolerated and active in patients with newly diagnosed, untreated, advanced-stage HL. This combination of nivolumab and AVD is actually being evaluated in phase II in early-stage unfavorable HL (NIVAHL, NCT03004833). Pembrolizumab is also being evaluated in combination with AVD (NCT03226249). 12.7 Conclusions and Future Strategies The reduction of dose and size of RT and more recently, PET-adapted strategies have reduced the burden of treatment used to treat early-stage HL and also defined a subpopulation that can benefit from early intensification. Unfortunately, there is no evidences that this could reduce long-term toxicities. Recently, three new drugs (brentuximab vedotin, nivolumab, and pembrolizumab) showed interesting results in the setting of relapsing patients [35–37]. These drugs are now also being actively evaluated in first-line for early-stage HL, either alone (i.e., in elderly patients) or in combination with AVD. Phase II data are promising, but only randomized phase III trial can change the standard of care in this highly curable group of patients. Finally, circulating cell-free DNA could emerge as a very interesting tool to refine response evaluation and better define cure [10]. References 1. Lister TA, Crowther D, Sutcliffe SB et al (1989) Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin’s disease: Cotswolds meeting. J Clin Oncol 7(11):1630–1636 2. Kostakoglu L, Cheson BD (2014) Current role of FDG PET/CT in lymphoma. Eur J Nucl Med Mol Imaging 41(5):1004–1027 3. Stevens WB, van Krieken JH, Mus RD et al (2012) Centralised multidisciplinary re-evaluation of diagnostic procedures in patients with newly diagnosed Hodgkin lymphoma. Ann Oncol 23(10):2676–2681 4. Eichenauer DA, Aleman BMP, Andre M et al (2018) Hodgkin lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 29(Suppl 4):iv19–iv29 5. El-Galaly TC, d’Amore F, Mylam KJ et al (2012) Routine bone marrow biopsy has little or no therapeutic consequence for positron emission tomography/computed tomography-staged treatment-naive patients with Hodgkin lymphoma. J Clin Oncol 30(36):4508–4514 6. Klimm B, Goergen H, Fuchs M et al (2013) Impact of risk factors on outcomes in early-stage Hodgkin’s lymphoma: an analysis of international staging definitions. Ann Oncol 24(12):3070–3076 7. Specht L, Nordentoft AM, Cold S, Clausen NT, Nissen NI (1988) Tumor burden as the most important prognostic factor in early stage Hodgkin’s disease. Relations to other prognostic factors and implications for choice of treatment. Cancer 61(8):1719–1727 8. Gobbi PG, Ghirardelli ML, Solcia M et al (2001) Image-aided estimate of tumor burden in Hodgkin’s disease: evidence of its primary prognostic importance. J Clin Oncol 19(5):1388–1394 9. Cottereau AS, Versari A, Loft A et al (2018) Prognostic value of baseline metabolic tumor volume in e arly-stage Hodgkin lymphoma in the standard arm of the H10 trial. Blood 131(13):1456–1463 10. Spina V, Bruscaggin A, Cuccaro A et al (2018) Circulating tumor DNA reveals genetics, clonal evolution, and residual disease in classical Hodgkin lymphoma. Blood 131(22):2413–2425 11. Schaapveld M, Aleman BM, van Eggermond AM et al (2015) Second cancer risk up to 40 years after treatment for Hodgkin’s lymphoma. N Engl J Med 373(26):2499–2511 12. Baxstrom K, Peterson BA, Lee C, Vogel RI, Blaes AH (2018) A pilot investigation on impact of participation in a long-term follow-up clinic (LTFU) on breast cancer and cardiovascular screening among women who received chest radiation for Hodgkin lymphoma. Support Care Cancer 26(7):2361–2368 13. Cutter DJ, Schaapveld M, Darby SC et al (2015) Risk of valvular heart disease after treatment for Hodgkin lymphoma. J Natl Cancer Inst 107(4):djv008 14. Hahn E, Jiang H, Ng A et al (2017) Late cardiac toxicity after mediastinal radiation therapy for Hodgkin lymphoma: contributions of coronary artery and whole heart dose-volume variables to risk prediction. Int J Radiat Oncol Biol Phys 98(5):1116–1123 15. Engert A, Schiller P, Josting A et al (2003) Involved- field radiotherapy is equally effective and less toxic compared with extended-field radiotherapy after four cycles of chemotherapy in patients with early-stage unfavorable Hodgkin’s lymphoma: results of the HD8 trial of the German Hodgkin’s Lymphoma Study Group. J Clin Oncol 21(19):3601–3608 12 Treatment of Early Unfavorable Hodgkin Lymphoma 16. Ferme C, Eghbali H, Meerwaldt JH et al (2007) Chemotherapy plus involved-field radiation in early-stage Hodgkin’s disease. N Engl J Med 357(19):1916–1927 17. Sasse S, Brockelmann PJ, Goergen H et al (2017) Long-term follow-up of contemporary treatment in early-stage Hodgkin lymphoma: updated analyses of the German Hodgkin Study Group HD7, HD8, HD10, and HD11 Trials. J Clin Oncol 35(18):1999–2007 18. Eich HT, Diehl V, Gorgen H et al (2010) Intensified chemotherapy and dose-reduced involved-field radiotherapy in patients with early unfavorable Hodgkin’s lymphoma: final analysis of the German Hodgkin Study Group HD11 trial. J Clin Oncol 28(27):4199–4206 19. Ferme C, Thomas J, Brice P et al (2017) ABVD or BEACOPPbaseline along with involved-field radiotherapy in early-stage Hodgkin Lymphoma with risk factors: Results of the European Organisation for Research and Treatment of Cancer (EORTC)-Groupe d’Etude des Lymphomes de l'Adulte (GELA) H9-U intergroup randomised trial. Eur J Cancer 81:45–55 20. von Tresckow B, Plutschow A, Fuchs M et al (2012) Dose-intensification in early unfavorable Hodgkin’s lymphoma: final analysis of the German Hodgkin Study Group HD14 trial. J Clin Oncol 30(9):907–913 21. Meyer RM, Gospodarowicz MK, Connors JM et al (2012) ABVD alone versus radiation-based therapy in limited-stage Hodgkin’s lymphoma. N Engl J Med 366(5):399–408 22. Gallamini A, Hutchings M, Rigacci L et al (2007) Early interim 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography is prognostically superior to international prognostic score in advanced-stage Hodgkin’s lymphoma: a report from a joint Italian- Danish study. J Clin Oncol 25(24):3746–3752 23. Simontacchi G, Filippi AR, Ciammella P et al (2015) Interim PET after two ABVD cycles in early-stage Hodgkin lymphoma: outcomes following the continuation of chemotherapy plus radiotherapy. Int J Radiat Oncol Biol Phys 92(5):1077–1083 24. Cheson BD, Fisher RI, Barrington SF et al (2014) Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 32(27):3059–3068 25. Barrington SF, Kirkwood AA, Franceschetto A et al (2016) PET-CT for staging and early response: results from the response-adapted therapy in advanced Hodgkin lymphoma study. Blood 127(12):1531–1538 26. Radford J, Illidge T, Counsell N et al (2015) Results of a trial of PET-directed therapy for early-stage Hodgkin’s lymphoma. N Engl J Med 372(17):1598–1607 247 27. Andre MPE, Girinsky T, Federico M et al (2017) Early positron emission tomography response-adapted treatment in Stage I and II Hodgkin lymphoma: final results of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol 35(16):1786–1794 28. Straus DJ, Jung SH, Pitcher B et al (2018) CALGB 50604: risk-adapted treatment of nonbulky early-stage Hodgkin lymphoma based on interim PET. Blood 132(10):1013–1021 29. Hoppe RT, Advani RH, Ai WZ et al (2017) Hodgkin Lymphoma Version 1.2017, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 15(5):608–638 30. Younes A, Connors JM, Park SI et al (2013) Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin’s lymphoma: a phase 1, open-label, dose-escalation study. Lancet Oncol 14(13):1348–1356 31. Fornecker L, Lazarovici J, Aurer I et al (2017) PET- based response after 2 cycles of Brentuximab Vedotin in combination with AVD for first-line treatment of unfavorable early-stage Hodgkin lymphoma: first analysis of the primary endpoint of breach, a randomized phase II Trial of Lysa-FIL-EORTC intergroup. Blood 130(Suppl 1):736 32. Kumar A, Casulo C, Advani RH et al (2017) A Pilot Study of Brentuximab Vedotin and AVD chemotherapy followed By 20 Gy involved-site radiotherapy in early stage, Unfavorable Risk Hodgkin Lymphoma. Blood 130(Suppl. 1):734 33. Ramchandren R, Fanale MA, Rueda A et al (2017) Nivolumab for newly diagnosed advanced-stage Classical Hodgkin Lymphoma (cHL): results from the phase 2 checkmate 205 study. Blood 130(Suppl 1):651 34. UK RAPID study: NCT 00003849. 35. Chen R, Zinzani PL, Fanale MA et al (2017) Phase II study of the efficacy and safety of Pembrolizumab for relapsed/refractory classic Hodgkin lymphoma. J Clin Oncol 35(19):2125–2132 36. Younes A, Gopal AK, Smith SE et al (2012) Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol 30(18):2183–2189 37. Younes A, Santoro A, Shipp M et al (2016) Nivolumab for classical Hodgkin’s lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol 17(9):1283–1294 38. Juweid ME, Stroobants S, Hoekstra OS et al (2007) Use of positron emission tomography for response assessment of lymphoma: consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma. J Clin Oncol 25(5):571–578 Treatment of Advanced-Stage Hodgkin Lymphoma 13 Alexander Fosså, René-Olivier Casasnovas, and Peter W. M. Johnson Contents 13.1 Introduction and Early History of Combination Chemotherapy 249 13.2 13.2.1 13.2.2 Fourth-Generation Regimens Hybrid and Alternating Regimens BEACOPP Escalated 251 251 251 13.3 ABVD or BEACOPP Escalated as Standard First-Line Treatment? 253 13.4 13.4.1 13.4.2 Outcome Prediction The International Prognostic Score Positron Emission Tomography 255 255 255 13.5 13.5.1 13.5.2 Response-Adapted Therapy De-escalation of Therapy in Early Responders Escalation of Therapy in Early Nonresponders 256 256 257 13.6 Introduction of Brentuximab Vedotin into First-Line Treatment 259 13.7 I ntroducing Programmed-Death-1 Inhibitors into First-Line Treatment 260 13.8 The Role of Radiotherapy 260 13.9 Summary 261 References A. Fosså Department of Oncology and National Resource Centre for Late Effects After Cancer Therapy, Oslo University Hospital, Oslo, Norway KG Jebsen Centre for B-cell Malignancies, University of Oslo, Oslo, Norway R.-O. Casasnovas Department of Haematology, University Hospital F. Mitterrand and INSERM1231, Dijon, France P. W. M. Johnson (*) Cancer Research UK Centre, University of Southampton, Southampton, UK e-mail: johnsonp@soton.ac.uk 261 13.1 Introduction and Early History of Combination Chemotherapy The definition of advanced stage in Hodgkin lymphoma (HL) has evolved over time. Megavoltage radiotherapy (RT) techniques proved efficacious in stage I and IIA disease in the 1950s and 1960s, whereas only few patients with stage III disease were cured by RT alone, despite extended fields of treatment [1]. At the © Springer Nature Switzerland AG 2020 A. Engert, A. Younes (eds.), Hodgkin Lymphoma, Hematologic Malignancies, https://doi.org/10.1007/978-3-030-32482-7_13 249 A. Fosså et al. 250 time, more than 95% of patients with stage IV HL succumbed to their disease within 5 years. The first encouraging trials on combination chemotherapy included patients with stages III and IV. Thus, from a historical perspective, advanced disease may be defined by risk groups where curative combination chemotherapy is planned as the primary treatment, while RT is either not used or not the major component. The definition of advanced disease has therefore varied between academic study groups and between trials. This should be borne in mind when evaluating treatment recommendations and results from trials. For most studies, stages IIB, III, and IV are considered advanced disease, while stage IIA is sometimes included, but only in the presence of other risk factors such as bulky disease or multiple sites of involvement. With the advent of more exact diagnostic tools and targeted treatment, the distinction between classical HL (cHL) and nodular lymphocyte- predominant HL has become more robust and more important for treatment. The current chapter covers the development of treatment for cHL only, recognizing that in the past this distinction was not as clear as it is today. The introduction by DeVita and coworkers of the MOPP regimen to treat patients with advanced HL was a milestone in oncology [2, 3]. MOPP resulted in long-term remission in nearly 50% of patients with stage III and IV disease and has been used for than 40 years. Bonadonna and coworkers were the first to report on the importance of anthracyclines in developing ABVD [4]. ABVD replaced MOPP as the preferred first-line treatment worldwide as the result of a series of randomized trials comparing ABVD, MOPP, and/or MOPP/ABVD alternating, sequential, or hybrid regimens [5–10]. The results were better for ABVD or ABVD-containing regimens than for MOPP alone, with failure-free (FFS) or event- free survival (EFS) rates at 5–10 years of 50–80% for ABVD-containing regimens, compared to 35.9% for MOPP in Bonadonna’s original trial and 50% in the Cancer and Leukemia Group B (CALGB) trial reported by Canellos in 1992 (Table 13.1). The acceptance of ABVD over MOPP and MOPP-like regimens during the 1980s and 1990s was not only motivated by its greater efficacy but also by concerns about toxicity. Follow-up of the early trials showed that irreversible gonadal dysfunction as well as acute leukemia occurred far Table 13.1 MOPP and ABVD in randomized trials Trial Bonadonna et al. [5] Santoro et al. [6] US Intergroup [7] Viviani et al. [8] Connors et al. [9] Year 1986 Combination regimen MOPP/ABVD alternating MOPP Number of patients 43 45 1987 3×MOPP-RT-3×MOPP 114 118 2003 3×ABVD-RT- 3×ABVD ABVD (6 cycles) MOPP/ABV hybrid (6 cycles) MOPP/ABVD alternating (6 cycles) MOPP/ABVD hybrid (6 cycles) MOPP/ABVD hybrid (8 cycles) MOPP/ABVD alternating. (8 cycles) 419 1996 1997 433 211 204 153 148 Outcome 64.6% (FFP) 83.9% (OS) 35.9% (FFP) 63.9% (OS) 62.8% (FFP) 77.4% (OS) 80.8% (FFP) 67.9% (OS) 63% (FFS) 82% (OS) 66% (FFS) 81% (OS) 67% (FFP) 74% (OS) 69% (FFP) 72% (OS) 71% (FFS) 81% (OS) 67% (FFS) 83% (OS) Follow-up and comments 8 years 7 years; (sub)total nodal irradiation in all patients 5 years; MDS and AML only in MOPP-treated patients 10 years; stage IB and IIA included 5 years; radiotherapy or prolonged chemotherapy after cycle 6 for PR (continued) 13 Treatment of Advanced-Stage Hodgkin Lymphoma 251 Table 13.1 (continued) Trial CALGB [10] Year 1992 Combination regimen ABVD Number of patients 115 MOPP 123 MOPP/ABVD alternating 123 Outcome 61% (FFS) 73% (OS) 50% (FFS) 66% (OS) 65% (FFS) 75% (OS) Follow-up and comments 5 years Abbreviations: CALGB Cancer and Leukemia Group B, GHSG German Hodgkin Study Group, FFS failure-free survival, FFP freedom from progression, FFTF freedom from treatment failure, OS overall survival, MDS myelodysplastic syndrome, AML acute myelogenous leukemia more often in patients treated with MOPP and MOPP-like regimens. With improved control of the lymphoma, there was an increasing need to balance the likelihood of cure and the risk of serious or fatal complications from treatment. This balance has since been a key concept in the development of better treatment options for advanced- stage cHL. ABVD is a safe outpatient regimen without the need for close white blood cell monitoring, is feasible in most adult patients up to the age of 60, and can be administered in less-developed healthcare systems [11]. However, bleomycin may cause fatal lung toxicity, especially in older patients, and a long-term higher risk of cardiac morbidity has been reported for patients treated with 6–8 cycles of ABVD [12, 13]. Furthermore, Canellos and coworkers reported the long-term outcome for 123 patients treated with ABVD for advanced cHL in the CALGB trial with a FFS of only 47% and overall survival (OS) 59% after 14 years [14]. Therefore, alternative approaches were developed to improve these results. consolidation RT as part of first-line treatment in a varying proportion of patients (Table 13.2). None of these studies has established any regimen as superior to ABVD, with the notable exception of the BEACOPP escalated regimen developed by the German Hodgkin Study Group (GHSG). 13.2.2 BEACOPP Escalated The development of BEACOPP was motivated by the recognition that dose intensity plays a role in chemotherapy of advanced HL. Hasenclever and coworkers developed a statistical model of doseresponse characteristics for drugs used in 706 patients treated with COPP (cyclophosphamide, vincristine, procarbazine, prednisone)/ABVDlike regimens [23]. The model was then used to simulate the effect of dose escalation and changes of schedule and architecture of COPP-ABVD and to design the BEACOPP regimen. G-CSF was mandatory to compensate for the myelotoxic effects. In a phase II study, the optimal doses of the BEACOPP baseline and BEACOPP escalated regimens were determined [24]. The subsequent 13.2 Fourth-Generation HD9 trial of the GHSG found the predicted doseRegimens response curve to be correct when comparing the original COPP/ABVD to BEACOPP baseline and 13.2.1 Hybrid and Alternating Regimens BEACOPP escalated [20]. Results from 1195 randomized patients showed a clear superiority of 8 Several academic groups developed combina- cycles of BEACOPP escalated over BEACOPP tion regimens containing different drugs with baseline and COPP/ABVD at 5 years. Importantly, known efficacy in HL, and many of these fourth- follow-up data at 10 years confirmed these results: generation regimens were tested in randomized with a median follow-up of 112 months, freedom trials against ABVD [15–22]. According to from treatment failure (FFTF) and OS rates were standards of the time, most of these trials used 64 and 75% in the COPP/ABVD group, 70 and A. Fosså et al. 252 Table 13.2 Fourth generation trials Trial GHSG HD6 [15] Year 2004 Intergroup Italy [16] 2005 Combination regimen COPP/ABV/IMEP hybrid (4 cycles) COPP/ABVD alternating (4 cycles) ABVD (6 cycles) Stanford V (12 weeks) UK Lymphoma Group LY09 [17] 2005 MOPPEBVCAD (6 cycles) ABVD (6–8 cycles) ChlVPP/EVA (6–8 cycles) UK and Italy [18] 2002 ChlVPP/PABlOE (3–4 cycles alternating) ChlVPP/EVA hybrid (6 cycles) VAPEC-B (11 weeks) UKNCRI [19] 2009 ABVD (6–8 cycles) Stanford V GHSG HD9 [20] GHSG HD12 [21] GHSG HD15 [22] 2003 2011 2012 COPP/ABVD alternating (8 cycles) BEACOPP baseline (8 cycles) BEACOPP escalated (8 cycles) BEACOPP escalated (8 cycles) BEACOPP escalated and baseline (4 + 4) Number of patients Outcome 223 54% (FFTF) 73% (OS) 245 56% (FFTF) 73% (OS) 122 78% (FFS) 90% (OS) 107 54% (FFS) 82% (OS) 106 81% (FFS) 89% (OS) 394 75% (EFS) 79% (FFP) 90% (OS) 112 77% (EFS) 84% (FFP) 89% (OS) 282 74% (EFS) 78% (FFP) 87% (OS) 144 82% (FFP) 78% (EFS) 89% (OS) 138 62% (FFP) 58% (EFS) 79% (OS) 261 76% (PFS) 90% (OS) 259 74% (PFS) 92% (OS) 260 69% (FFTF) 83% (OS) 469 466 836 834 76% (FFTF) 88% (OS) 87% (FFTF) 91% (OS) 86.4%(FFTF) 92% (OS) 84.8% (FFTF) 90.3% (OS) Follow-up and comments 7 years 5 years; radiotherapy to initial bulk and residual mass 3 years; stages I and II included 5 years; radiotherapy to initial bulk and residual mass 5 years; radiotherapy to initial bulk and splenic deposits; stage I and II disease included 5 years; radiotherapy to initial bulk and residual mass 5 years; second randomization to radiotherapy (initial bulk or residual disease) versus observation 5 years; radiotherapy to PET positive residuals only BEACOPP escalated 705 84.4% (FFTF); (8 cycles) 91.9% (OS) BEACOPP escalated 711 89% (FFTF) (6 cycles) 95.3% (OS) BEACOPP-14 710 85.4% (FFTF) (8 cycles) 94.5%/(OS) Abbreviations: UKNCRI United Kingdom National Cancer Research Institute Lymphoma Group, GHSG German Hodgkin Study Group, FFS failure-free survival, FFP freedom from progression, FFTF freedom from treatment failure, EFS event-free survival, PFS progression-free survival, OS overall survival 13 Treatment of Advanced-Stage Hodgkin Lymphoma 80% in the BEACOPP baseline group, and 82 and 86% in the BEACOPP escalated group, respectively [25]. However, BEACOPP escalated is associated with higher rates of acute and long-term toxicity. The high rate of secondary malignancies, including myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) and solid cancers, and high rates of infertility could be attributed to the higher doses of alkylating agents and the frequent use of RT in the HD9 trial [20, 25]. The subsequent GHSG HD12 trial aimed at de- escalating treatment by comparing four courses of BEACOPP escalated with four courses of escalated and four courses of baseline BEACOPP (“4 + 4”) [21]. The role of RT was tested by a second randomization of consolidating radiation to initial bulky and residual disease versus no RT. At 5 years, OS was 91%, FFTF 85.5%, and progression-free survival (PFS) 86.2% with no statistical difference between 8 cycles of BEACOPP escalated and the 4 + 4 arm but no apparent benefit in terms of toxicity with the reduced regimen. Because a number of patients randomized to the arm without RT were in fact irradiated based on recommendations by a blinded expert panel, the conclusions to be drawn from this part of the trial are limited. Since there was no relevant benefit in terms of toxicity in the 4 + 4 treated patients, 8 cycles of BEACOPP escalated remained standard for advanced-stage HL patients in the GHSG. Recent long-term updates of both the HD9 and 12 trials confirm the superior initial results for BEACOPP escalated [26]. The subsequent HD15 study also tested de- escalation of chemotherapy with a reduction in the number of cycles from 8 to 6 and the introduction of a dose-dense BEACOPP baseline regimen (BEACOPP-14) [22]. In addition, PET-guided omission of RT to residual disease was investigated. A total of 2182 patients were randomized among the 3 study arms. Surprisingly, when comparing 6 cycles of BEACOPP escalated with 8 cycles, both PFS (90.3% versus 85.6%) and OS (95.3% versus 91.9%) were significantly better with the reduced number of cycles. With omission of RT in cases of PET- 253 negative residual masses, only 11% of all patients received additional RT without compromising tumor control, and the negative predictive value for the end of treatment PET at 12 months was 94.1% [27]. In summary, HD15 established six cycles of BEACOPP escalated as a new standard of care to be tested further in PET response- adapted trials (see below). With extensive evidence from clinical trials, BEACOPP escalated is a highly effective regimen for patients with advanced HL. Acute toxicity requires monitoring of patients between cycles, hospitalization in around one third of patients, and vigilance for potentially lethal neutropenic infections. Special attention should be paid to patients above the age of 50 years and patients of poor performance status at start of treatment. With the reduction of cycle numbers and less use of consolidation RT, rates of secondary malignancies seem to be decreasing, but determining the true rate of such complications will need longer observation [26]. Infertility in both women and men treated with BEACOPP is still a concern [28]. 13.3 BVD or BEACOPP Escalated A as Standard First-Line Treatment? These developments led to the emergence of two alternative strategies for the treatment of advanced HL: balancing cure rates and toxicity, the first strategy proposed ABVD as the standard front line regimen, with salvage treatment, high- dose chemotherapy (HDCT), and autologous stem cell transplantation (ASCT) for those patients failing initial therapy. With this strategy, the majority of patients could be cured with ABVD without exposing them to the toxicity of BEACOPP. The second strategy used BEACOPP escalated as first-line treatment, aiming to cure as many patients as possible with first-line therapy, but accepting more toxicity for those patients who might have been cured with a less intensive approach. Data are now available from direct comparative trails and from meta-analyses to address this question. A. Fosså et al. 254 Table 13.3 ABVD versus BEACOPP in direct comparisons Combination Number of Study Year regimen patients Disease control p HD 2000 [29] 2009 ABVD 99 68% (PFS) 0.038* BEACOPP 98 81% (4 esc +2 bas) CEC 98 78% 168 73% (FFFP) 0.004 Michelangelo- 2011 ABVD GITIL-IIL BEACOPP (4 163 85% [30] esc + 4 bas) 91% 84% 89% ns Follow-up and comments 5 years 7 years; salvage treatment specified 4 years; EFS primary endpoint ABVD (8 275 72.8% (PFS) 0.005 86.7% ns cycles) BEACOPP 274 83.4% 90.3% (4 esc + 4 bas) LYSA H34 2014 ABVD 77 75% (PFS) 0.007 92% 0.06 5 years IPS 0–2 [32] BEACOPP 68 93% 99% (4 esc + 4 bas) Abbreviations: GITIL Gruppo Italiano di Terapie Innovative nei Linfomi, IIL Intergruppo Italiano Linfomi, LYSA Lymphoma Study Association EORTC European Organization for Research and Treatment of Cancer, IPS International Prognostic Score, CEC cyclophosphamide, lomustine, vindesine, melphalan, prednisone, epidoxorubicin, vincristine, procarbazine, vinblastine, bleomycin, FFFP freedom from first progression, EFS event-free survival, PFS progressionfree survival, p p-value for comparison, esc escalated, bas baseline * BEACOPP versus ABVD EORTC 20012 IPS 3–7 [31] 2016 Overall survival p 84% ns 92% Four studies have been conducted comparing these two approaches, all smaller and so far with shorter follow-up than the HD9 trial. All studies compare four escalated BEACOPP followed by two or four baseline BEACOPP with six to eight cycles of ABVD (Table 13.3). The Italian HD2000 trial enrolled 307 patients in 3 different treatment arms showing a significant superiority of BEACOPP (4+2 fashion) over 6 cycles of ABVD in terms of PFS but not for OS [29]. At 5 years, the PFS rate was 68% for ABVD and 81% for BEACOPP: OS was 84% for ABVD and 92% for BEACOPP, respectively. The data of this trial were updated at 10 years follow-up, and the authors were not able to confirm the superiority of BEACOPP over ABVD in terms of PFS, mainly because of higher mortality from second malignancies observed after BEACOPP [33]. The Michelangelo Foundation, the Gruppo Italiano di Terapie Innovative nei Linfomi (GITIL), and the Intergruppo Italiano Linfomi (IIL) study compared 6–8 courses of ABVD and BEACOPP given in 4 + 4 fashion plus preplanned salvage with HDCT [30]. Patients with a higher risk profile based on international prognostic score (IPS) of 3 and more were included. Two thirds of the patients also received RT. The final analysis showed a 7-year rate of freedom from first progression (FFFP) of 85% in patients who received initial treatment with BEACOPP and 73% for those who received ABVD (p = 0.004). A total of 65 patients (20 in the BEACOPP group and 45 in the ABVD group) needed HDCT. After completion of the planned treatment including salvage therapy, the 7-year OS rates were 89 and 84%, respectively (p = 0.39). This trial was not powered to detect differences in OS, and the conclusion on overall treatment outcome should be cautioned. The slightly larger intergroup trial organized by the EORTC had a similar design as the Michelangelo-GITIL-IIL study [31]; 8 courses of ABVD were compared to BEACOPP 4 + 4 with no RT allowed. With a median follow-up of 3.6 years at the time of the final report, the 4-year rates for EFS and OS were similar in ABVD- treated (63.7% and 86.7%, respectively) and BEACOPP-treated patients (69.3% and 91.5%). However, the secondary endpoint, PFS, was significantly lower in the ABVD than in the BEACOPP arm (72.8% versus 83.4%, p = 0.0052). There were no clear differences in toxicity between the two arms. Patients with low-risk advanced-stage disease (IPS 0–2) were enrolled in the H34 trial conducted by the Lymphoma Study Association (LYSA) [32]. With 150 patients randomized in 13 Treatment of Advanced-Stage Hodgkin Lymphoma 255 this trial, the complete remission rate was 85% for ABVD and 90% for BEACOPP. With a median follow-up of 5.5 years, 7 patients died: 6 treated with ABVD and 1 with BEACOPP. The PFS at 5 years was 75% and 93% (p = 0.007) and the OS 92% and 99% (p = 0.06) for ABVD- and BEACOPP-treated patients. Although the number of patients recruited in this trial was rather small, these results suggest that BEACOPP is also more effective than ABVD in advanced- stage patients with lower risk. All trials comparing ABVD and BEACOPP directly are smaller than the GHSG trials and evaluated different numbers of BEACOPP escalated (4 + 4 or 4 + 2, escalated, and baseline, respectively). 6 cycles of escalated BEACOPP have been shown by the GHSG to represent the most effective strategy. Since there was uncertainty regarding the difference in OS between ABVD and BEACOPP, a network meta-analysis was performed to indirectly compare these and other regimens [34]. The final analysis included nearly 10,000 patients from 14 different trials. Reconstructed survival data suggested that 6 cycles of BEACOPP escalated have a 10% advantage over ABVD in terms of OS at 5 years (95% confidence interval 3–15%), offering advancedstage HL patients the highest chance of cure. Another more recent meta-analysis with data from four of the trials mentioned above (and including one trial comparing ABVD and BEACOPP in early unfavorable disease) confirmed the superiority of BEACOPP escalated over ABVD in term of PFS and OS [35]. There was a significantly increased occurrence of MDS or AML in BEACOPP-based strategies (relative risk 3.90, p = 0.02), but not for second malignancies in total. The risk of infertility could not be assessed by these meta-analyses due to lack of data. order to balance efficacy and toxicity. The development of the IPS paralleled the quest for more effective regimens than ABVD and was aimed to further assess each patient’s risk of treatment failure under ABVD- and ABVD-like regimens [36]. The score was derived from 5141 patients who had been treated with ABVD-like regimens with or without RT. Seven factors had similar independent prognostic effects: serum albumin of less than 4 g/dL, hemoglobin level of less than 10.5 g/ dL, male sex, age of 45 years or older, stage IV disease (according to the Ann Arbor classification), leukocytosis (white cell count of at least 15 × 10−9 L), and lymphocytopenia (lymphocyte count of less than 0.6 × 10−9 or less than 8% of white-cell count). As outlined, several studies evaluating BEACOPP escalated have selected patients not only based on stage and B symptoms, but also on a higher IPS. It is assumed that the more intensive treatment will have the greatest effect in high-risk patients. This is in part supported by the results of the HD9 trial, where the absolute benefit in terms of improved OS in those treated with BEACOPP escalated seems greater in intermediate risk than in low-risk patients, although not in the high-risk group [25]. The LYSA H34 results in low-risk patients suggest a significant 18% benefit in PFS rates and a borderline significant improvement in OS of 9%, both at 5 years, but this requires confirmation [32]. 13.4 Outcome Prediction 13.4.1 T he International Prognostic Score With the choice between ABVD and BEACOPP, it would be preferable to treat each advanced cHL patient according to their individual risk in 13.4.2 Positron Emission Tomography Assessment of the risk of treatment failure by IPS has been partly displaced by early response evaluation. To determine the optimal amount of treatment needed, functional imaging in the form of FDG-PET has been developed to provide an early indication of chemosensitivity in HL. PET is discussed in detail elsewhere in this book (see Chap. 7). In patients with mostly advanced disease, retrospective studies showed that the early PET response (after two cycles of ABVD) overshadowed the prognostic value of the IPS and thus could be an important tool for response- A. Fosså et al. 256 adapted treatment planning in advanced HL [37]. The utility of FDG-PET has been facilitated by development of a highly reproducible 5-point scale, the Deauville scale, for reporting results [38]. Several recent studies have tested early response evaluation by FDG-PET as a means of adjusting subsequent therapy according to the response to initial treatment. Strategies based on initial ABVD or BEACOPP have helped to define new standards of care in which each patient receives as much therapy as deemed necessary. Table 13.4 Response adapted therapy in randomized trials %PET-2 Upfront Number of negative/ positive Study Year regimen patients RATHL 2016 ABVD 1203 86 [39] DS 1-3 13.5 Response-Adapted Therapy 13.5.1 De-escalation of Therapy in Early Responders Groups using either ABVD or BEACOPP as initial therapy have aimed to reduce treatment intensity in patients with a negative interim PET, by omitting potentially toxic components of the regimens, by reducing the number of cycles, or by omitting RT (Table 13.4). In the international RATHL trial, all patients initially received two cycles of ABVD [39]. Follow-up and comments 3 years; ABVD vs AVD in PET-2 negative disease 16 67.5% (BEACOPP) 87.8% BEACOPP DS 4-5 escalated/-14 in PET-2 positive disease 2018 ABVD 782 81 87% (ABVD) 99% 3 years; with or GITIL/ DS 1-3 without RT in bulky FIL0607 PET-2 negative [40] disease 19 63% (R-BEACOPP) 89% BEACOPP with or DS 4-5 57% (BEACOPP) without R in PET-2 positive disease 2016 BEACOPP 275 52 92.2% 97.7% 5 years; 6–8 vs 4 GHSG esc DS 1-2 (4×BEACOPPesc) cycles HD18 [41] 90.8% 95.4% BEACOPP escalated in PET-2 (6–8×BEACOPPesc) negative disease 48 88.4% 93.6% BEACOPP DS 3-5 (R-BEACOPPesc) escalated with or 96.4% without R in PET-2 89.7% positive disease (BEACOPPesc) LYSA 2018 BEACOPP 823 87 89.4% (ABVD) 96.4% 5 years; modified AHL2011 esc DS 1-3 Deauville criteria for PET-2, OS 13 88.4% 99% similar in DS 4-5 (BEACOPPesc) PET-driven and standard arm Abbreviations: RATHL Response adapted therapy in Hodgkin lymphoma, GITIL/FIL Gruppo Italiano Terapie Innovative Linfomi/Fondazione Italiana Linfomi, LYSA Lymphoma Study Association, GHSG German Hodgkin Study Group, PFS progression-free survival, OS overall survival, DS Deauville score, PET-2 PET scan performed after 2 cycles of therapy, BEACOPPesc BEACOPP escalated, R Rituximab PFS 85% (ABVD) 84.4% (AVD) OS 97.2% 97.6% 13 Treatment of Advanced-Stage Hodgkin Lymphoma Using a Deauville score cut-off between 3 and 4, 83.7% of the patients were interim PET negative and were randomized. In the experimental arm, bleomycin was not given in the remaining four cycles. The results showed 3-year PFS rates of 85.7% and 84.4%, respectively, in the standard ABVD and AVD groups. Pulmonary toxicity was reduced in patients treated with AVD in cycles 3 through 6. Thus, bleomycin is redundant in advanced-stage patients who have achieved a complete metabolic response after two cycles of chemotherapy. In patients with advanced HL who have a negative PET, defined as Deauville scores 1–3, after two and six cycles of ABVD, the GITIL/ Fondazione Italiana Linfomi (FIL) HD0607 trial demonstrated that consolidation RT to initially bulky lesions can be omitted without a decrease in tumor control at 3 years [40]. The 3-year PFS was 87% in the interim PET-negative group. The proportions of interim PET-negative patients in the RATHL and GITL/FIL HD0607 studies and 3-year PFS rates are remarkably similar. They are comparable to other prospective phase II trials using the same approach [42, 43]. However, the negative predictive value of interim PET-CT in these prospective trials appears lower than anticipated from previous retrospective studies using non-standardized criteria for reporting PET results. This means that the largest number of treatment failures in advanced-stage HL treated initially with ABVD will occur in the interim PET-negative group. Interim PET-CT has also been used to deescalate therapy in early responders to BEACOPP escalated. Using the FDG uptake in the mediastinal blood pool as reference, corresponding to Deauville scores of 1 and 2, the randomized GHSG HD18 trial demonstrated that the number of cycles of BEACOPP could be reduced from six to four in patients with a negative interim PET after two cycles [41]. With 1005 out of 1945 randomized patients (52%) having a negative interim PET by these criteria, the HD18 trial indicated an excellent 5-year OS rate of 95% and a significant reduction of severe acute hematological and non-hematological toxicities. The GHSG later provided post hoc evidence that the excellent outcome of PET- 257 negative patients also holds for those with an interim Deauville score of 3, and despite the fact that these had all received six cycles of BEACOPP escalated in the trail, a total of four escalated BEACOPPs to patients with an interim score of 1–3 are currently recommended [44]. The randomized LYSA AHL2011 trial evaluated whether a PET-driven strategy allows for a tailored shift from BEACOPP escalated to ABVD in advanced HL [45]. In the experimental arm, patients with a negative PET after two cycles of BEACOPP escalated completed treatment with four cycles of ABVD, while the interim PET- positive patients continued with four cycles of BEACOPP escalated. Patients assigned to the standard arm received a total of six cycles of BEACOPP escalated. After a median observation time of 50 months, 5-year PFS rates did not differ, 86.5% and 85.7% in the standard and experimental arms, respectively. Using a Deauville score cut-off between 3 and 4 in the experimental arm, 84% of patients received 2 escalated BEACOPP and 4 ABVD with a significant reduction in toxicity. Thus, it appears possible to switch to ABVD on the basis of a negative interim PET after two cycles of escalated BEACOPP without loss of tumor control. By extrapolation from the RATHL study, it may be possible to switch to AVD and thereby avoid the risk of continued bleomycin exposure. The LYSA AHL2011 used a modified Deauville score for assessment of interim PET-CT defining score 4 and 5 as a residual lesion uptake equal or higher than 140% and 200% of the liver uptake, respectively. These more stringent criteria may explain the lower rate of interim PET-positive patients in the AHL2011 (12.6%) than in the HD18 trial (24%) and the higher treatment failure rate in the PET-positive group in AHL2011 compared to HD18 study. 13.5.2 E scalation of Therapy in Early Nonresponders Several groups tested prospectively the approach of escalating treatment in patients not responding to two cycles of ABVD as defined by PET posi- 258 tivity (Table 13.4). With the limitations mentioned above, based on the historical data, these patients have a very poor outcome with ABVD or ABVD-like therapy. The 2- or 3-year PFS is reported between 6% and 38% [46]. Most investigators have therefore considered it unethical in these patients to compare any experimental therapy to ABVD in a randomized fashion. The RATHL trial tested the escalation to either BEACOPP escalated four cycles or BEACOPP-14 six cycles in interim PET-positive patients [39]. Of the 182 patients with positive findings on interim PET-CT scans according to protocol, 94 received BEACOPP-14 and 78 received escalated BEACOPP. The results of a third PET-CT scan were available for 160 patients, of whom 119 (74.4%) had negative findings. The 3-year PFS rate for the group as a whole was 67.5%, and the OS rate was 87.8%. Similar results were reported in the GITIL/ FIL HD0607 trial [40]. 149 of 150 patients with interim PET-positive results continued on BEACOPP (4 escalated and 4 baseline) with or without the addition of rituximab. After four BEACOPP escalated, a PET evaluation was performed in 136 patients. At the time of the report, disease progression was registered in 27 of 108 PET-negative scans compared with 25 of 28 PET- positive scans. The 3-year PFS rate was 60%, and the 3-year OS rate was 89% in the interim PET- positive group. The American South West Oncology Group (SWOG) followed the same principles of escalating to six cycles of BEACOPP escalated after ABVD with similar results for the interim PET- positive group compared to RATHL and GITIL/ FIL HD0607 trials [42]. Escalation to an alternative regimen consisting of ifosfamide, gemcitabine and vinorelbine (IGEV) followed by HDCT was pursued in the Italian HD0801 study [43]. In an intention-to-treat analysis, the authors reported for the PET-positive patients (excluding those with Deauville score 3) a 2-year PFS of 75%. Taking together the shift from ABVD to BEACOPP escalated or variants thereof seems justified in interim PET-positive patients. Whether other salvage regimens including HDCT A. Fosså et al. might improve the outcomes further is unknown at present. Nonetheless, the results remain suboptimal, and further improvements, possibly by incorporation of novel drugs, are needed. Following the success with initial BEACOPP escalated in the HD9, HD12, and HD15 trials, the GHSG tested whether it might be possible to improve the results by adding rituximab, a monoclonal antibody binding to CD-20 on the surface of B cells, in patients with interim PET-positive disease [47]. The rationale is derived from the recognition of a minority of cHL cases with CD-20-positive Hodgkin or Reed-Sternberg cells and the possible benefit of targeting normal B cell in the tumor microenvironment. In the HD18 trial, patients with interim PET-positive disease (Deauville score 3–5) after two cycles of escalated BEACOPP were randomized to six further cycles with or without rituximab. The PFS rates at 3 years for PET-positive patients were 93.0% and 91.4% with or without rituximab, respectively, better than expected from the previous HD15 trial and without any benefit of adding rituximab. Patients with an interim Deauville score 4 (post hoc analysis of HD18) or 4–5 (LYSA AHL2011) after 2 BEACOPP escalated have reduced PFS rates compared to interim PET- negative patients with a score of 1–3. As mentioned, a later post hoc analysis of the HD18 study showed that in patients receiving 6 cycles of BEACOPP escalated, 3-year PFS rates were 92.2%, 95.9%, and 87.6% with interim PET scores of 1–2, 3, and 4, respectively [44]. The univariate hazard ratio (HR) for PFS in patients with score 4 versus score 1–3 was 2.3 (p = 0.002). Deauville score of 4 was the only factor remaining significant for PFS in a multivariate analysis including the associated baseline risk factors. In the LYSA AHL 2011 trial, using more stringent definitions of Deauville score 4 and 5, interim PET positivity was associated to a higher risk of relapse or progression with 5-year PFS of 70.7% versus 88.9% and a HR = 3.59 (p < 0.0001). Whether these results for interim PET-positive patients after initial BEACOPP therapy can be improved, i.e., by the incorporation of novel drugs, has not been tested yet. 13 Treatment of Advanced-Stage Hodgkin Lymphoma The concept of response-adapted therapy in advanced-stage HL has considerably changed the way in which patients are treated. Unfortunately, there is no direct comparison of strategies starting with ABVD and escalating in poor responders versus starting with BEACOPP escalated and reducing treatment in the early responders. 13.6 Introduction of Brentuximab Vedotin into First-Line Treatment With the approval of brentuximab vedotin (BV) for relapsed and refractory disease (see Chap. 21), a novel targeted drug has been introduced into the treatment of cHL. This has shown an excellent balance of efficacy and tolerability in persistent or recurrent disease [48]. Therefore, BV is an ideal candidate to improve both the ABVD and the BEACOPP regimens. BV was initially combined with ABVD in a phase I study; however, life-threatening pulmonary toxicity in this bleomycin-containing combination was observed [49]. BV at a fixed dose (1.2 mg/kg body weight) was given safely with bleomycin-deleted AVD (given the name A+AVD, as Adcetris, the proprietory name for BV) to 26 patients. 25 of the 26 (96%) had complete response after treatment. Neuropathy, probably as a result of coadministration of two microtubule-disrupting agents (monomethyl auristatin E and vinblastine), neutropenia and complications thereof, including the need to add growth factors in a number of patients, were noted as relevant toxicities. In a recent update on long-term outcome, the 5-year FFS and OS were 79% and 92% after ABVD plus BV and 92% and 100% after A+AVD, respectively [50]. After the initial encouraging results with A+AVD, this regimen has been tested in a large company-sponsored trial, comparing the new regimen to ABVD [51]. Patients with stage III and IV disease were entered and interim PET-CT after two cycles guided an optional switch to alternative frontline therapy at the treating physician’s discretion, but only for patients with a Deauville score of 5. The primary endpoint was modified 259 PFS, defined as time to disease progression, death, or modified progression (with the latter defined as evidence of non-complete response after completion of frontline therapy according to review by an independent committee, followed by subsequent anticancer therapy). With 1334 randomized patients and a median follow-up of 24.6 months, the 2-year modified PFS rates in the A+AVD and ABVD groups were 82.1% and 77.2%, respectively, a difference of 4.9 percentage points (p = 0.04). There was higher rate of febrile neutropenia in the A+AVD group, and growth factor support was introduced as mandatory during the course of the trial. There was also more severe neuropathy in the experimental arm, but as reported for other BV trials, this appeared to be reversible in most patients. As expected from the omission of bleomycin, lung toxicity was reduced. These results produced a debate as to whether A+AVD should be accepted as a new standard of care. Follow-up is short, and the new endpoint, incorporating into the definition of progression any treatment given to patients with residual PETpositive disease (Deauville scores 3–5), hampers comparison with other trials. With a modest difference between treatment arms, increased toxicity, and the absence of a documented survival benefit, the same principles as in the debate over ABVD and BEACOPP will apply. Another consideration is the considerable drug cost of BV and expense of the necessary growth factors. An interesting aspect of the Echelon-1 trial is the prospective less stringent approach to PET- guided adaptation, where patients with an interim PET-CT of 4 or 5 were either planned to continue treatment with A+AVD or ABVD (Deauville score 4) or allowed to do so as an alternative to intensive chemotherapy (Deauville score 5). The data thus reflect the outcome of ABVD-treated interim PET-positive patients in the modern era, using PET-CT in a prospective way and with uniform criteria comparable to other studies [52]. PET positivity rates were strikingly lower than in other similar studies, with Deauville ≥4 found in 7% (47/644) in the A+AVD arm and 9% (58/670) with ABVD; 5 patients with a Deauville score of 5 switched to alternative frontline therapy. Subgroup analyses of the ABVD arm showed a A. Fosså et al. 260 2-year modified PFS rate of 80.9% versus 42.0% for interim PET-negative and PET-positive patients, respectively. Following the aim to improve tolerability while maintaining efficacy, the GHSG has modified the BEACOPP regimen and introduced BV. A randomized phase II trial testing six cycles of two variants of BEACOPP was published recently: in one arm, vincristine was replaced by BV and bleomycin omitted (BrECAPP) [53]. A more experimental regimen additionally replaced dacarbazine for procarbazine and short-term dexamethasone instead of long-term prednisone (BrECADD). 104 patients were enrolled to the study (52 were assigned to each study arm). Complete responses were seen at completion of BrECAPP and BrECADD in 86% and 88% of patients, respectively. Particularly, the BrECADD regimen was associated with a more favorable toxicity profile and therefore selected for comparison to standard BEACOPP escalated in advanced cHL in the ongoing HD21 trial (NCT02661503). This trial is testing 4/6 cycles of escalated BEACOPP (in a PET response- adapted design) against 4/6 cycles of BrECADD. 13.7 Introducing Programmed- Death-1 Inhibitors into First-Line Treatment The second class of drugs recently introduced for relapsed and refractory cHL is the checkpoint inhibitors targeting programmed-death receptor (PD) 1, on the surface of cells in the microenvironment of cHL. It appears that Hodgkin and ReedSternberg cells by expression of the PD-ligand (PD-L)-1 and PD-L2 orchestrate the tissue microenvironment for tumor survival and growth (reviewed in Chap. 22). These mechanisms seem to be operable also in previously untreated cases [54]. Studies are underway to explore the effect of PD-1 inhibition also in the context of first-line treatment of advanced disease. So far, no results are reported. An initial study using nivolumab as sole initial therapy prior to the addition of AVD showed a response rate of 69% for monotherapy and promising short term outcomes, with PFS of 92% at 9 months [55]. 13.8 The Role of Radiotherapy The use of RT in advanced-stage HL has evolved over time, from subtotal or total nodal RT (i.e., treating also areas of initial possible microscopic disease) to involved-field RT (i.e., treating only areas of initial macroscopic disease) or as RT in situations associated with a higher risk of local relapse (most often site of initial bulky lesions or residual macroscopic disease possibly representing active tumor). The role of consolidation RT for advanced HL also depends on the efficacy of the prior chemotherapy (see Chap. 9 for further details). After MOPP or MOPP-like regimens, there appeared to be a potential advantage of IFRT in a meta-analysis of 16 randomized studies, whereas this advantage is not evident after ABVD or ABVD-like regimens [56, 57]. A randomized EORTC study demonstrated that consolidation IFRT did not improve outcomes in patients in complete remission after six to eight courses of MOPPABV, but potentially improved the outcome of patients with a partial response [58]. A randomized Groupe d’Etude des Lymphomes de l’Adulte (GELA) trial showed that consolidation with subtotal or total nodal RT for patients in remission after doxorubicin-containing systemic treatment was not superior to two additional cycles of chemotherapy [59]. Thus, patients achieving a complete radiological response with ABVD or ABVD-like regimens do not need consolidation RT. In current treatment algorithms, the chemosensitivity and quality of remission in each individual patient are assessed by FDG-PET, either as an interim PET during or a PET done at the end of treatment. PET results may be especially helpful in assessing the need for consolidation in situations with residual fibrotic masses after chemotherapy. The GITIL/FIL HD0607 trial randomized patients with advanced HL with a large nodal mass at diagnosis (≥5 cm) and a negative PET after two and six cycles of ABVD to RT of the site of the initial large mass or observation alone [40]. In 296 randomized patients, there was no significant PFS improvement at 3 years, 97% versus 93%, respectively (p = 0.29). Together, patients treated with ABVD that are in 13 Treatment of Advanced-Stage Hodgkin Lymphoma 261 complete remission by radiological criteria or PET negative after two cycles can safely omit RT, even in presence of residual masses. Whether certain patients with residual masses that are PET negative at the end of treatment (in the absence of any interim PET) or patients with interim or end of treatment positive PET in the context of ABVD benefit from the addition of RT has not been analyzed systematically. The HD15 trial prospectively analyzed the omission of RT in cases of PET-negative residual masses after six or eight cycles of BEACOPP [27]. All patients with residual disease of ≥2.5 cm after chemotherapy were evaluated using additional PET and based on the criteria at the time; those with a PET-positive result were irradiated to the site of residual disease. Only 11% of all patients received additional RT without compromising tumor control, and the negative predictive value for the end of treatment PET at 12 months was 94.1%. PFS at 4 years was similar for patients without residual disease and patients with PET- negative residuals, 92.1% and 92.6%, respectively, showing that RT can be safely omitted in both situations. PFS for PET-negative or PET- positive patients was 92.6% and 86.2% at 48 months (p = 0.022). Thus, a positive PET after chemotherapy was associated with higher risk of subsequent treatment failure, even though PET- positive patients were treated with additional RT. The frequency and pattern of relapses still suggest that local RT to PET-positive residual disease is sufficient for these patients [60]. omission of bleomycin and/or RT is possible in interim PET-negative patients. In case of an inadequate response, a shift to BEACOPP escalated may still cure a reasonable number of patients, subjecting only a minority of patients to the increased toxicity associated with BEACOPP. Similarly, the total number of cycles can be reduced from six to four or therapy switched to four ABVD in patients with interim negative PET results after two cycles of BEACOPP escalated. RT can be safely omitted in BEACOPP-treated patients with an end of treatment negative PET. With still short follow-up, the OS in either approach is excellent, with the interim PET-positive group after ABVD representing a candidate group for implementation of novel approaches. Apart from these more personalized treatment strategies, early results from a combination of BV with AVD show modest improvements in disease control but increased toxicity and costs. BV is also tested in the context of a modified BEACOPP regimen to enhance tolerability. After decades of substantial but slow advances in the treatment of advanced-stage HL, personalized treatment strategies have resulted in better treatment options for our patients. Targeted and immunological approaches may improve results further in the near future. 13.9 Summary Advanced-stage HL has become a curable disease for the majority of patients, and treatment decisions need to take into account the risk of serious long-term consequences of therapy. After a decade of debate whether first-line treatment with six to eight cycles of ABVD or BEACOPP escalated best balances the likelihood of cure and risk of complications, individualized treatment based on early response to chemotherapy has now become a standard in many developed countries. Starting with ABVD, de-escalation by References 1. Kaplan HS (1972) Hodgkin’s disease. Harvard University Press, Cambridge, MA. 452 p 2. Devita VT Jr, Serpick AA, Carbone PP (1970) Combination chemotherapy in the treatment of advanced Hodgkin’s disease. Ann Intern Med 73(6):881–895 3. DeVita VT Jr, Simon RM, Hubbard SM, Young RC, Berard CW, Moxley JH 3rd et al (1980) Curability of advanced Hodgkin’s disease with chemotherapy. Long-term follow-up of MOPP-treated patients at the National Cancer Institute. Ann Intern Med 92(5):587–595 4. Bonadonna G, Zucali R, Monfardini S, De Lena M, Uslenghi C (1975) Combination chemotherapy of Hodgkin’s disease with adriamycin, bleomycin, vinblastine, and imidazole carboxamide versus MOPP. Cancer 36(1):252–259 5. Bonadonna G, Valagussa P, Santoro A (1986) Alternating non-cross-resistant combination chemotherapy or MOPP in stage IV Hodgkin’s disease. A report of 8-year results. Ann Intern Med 104(6):739–746 262 6. Santoro A, Bonadonna G, Valagussa P, Zucali R, Viviani S, Villani F et al (1987) Long-term results of combined chemotherapy-radiotherapy approach in Hodgkin’s disease: superiority of ABVD plus radiotherapy versus MOPP plus radiotherapy. J Clin Oncol 5(1):27–37 7. Duggan DB, Petroni GR, Johnson JL, Glick JH, Fisher RI, Connors JM et al (2003) Randomized comparison of ABVD and MOPP/ABV hybrid for the treatment of advanced Hodgkin’s disease: report of an intergroup trial. J Clin Oncol 21(4):607–614 8. Viviani S, Bonadonna G, Santoro A, Bonfante V, Zanini M, Devizzi L et al (1996) Alternating versus hybrid MOPP and ABVD combinations in advanced Hodgkin’s disease: ten-year results. J Clin Oncol 14(5):1421–1430 9. Connors JM, Klimo P, Adams G, Burns BF, Cooper I, Meyer RM et al (1997) Treatment of advanced Hodgkin’s disease with chemotherapy--comparison of MOPP/ABV hybrid regimen with alternating courses of MOPP and ABVD: a report from the National Cancer Institute of Canada clinical trials group. J Clin Oncol 15(4):1638–1645 10. Canellos GP, Anderson JR, Propert KJ, Nissen N, Cooper MR, Henderson ES et al (1992) Chemotherapy of advanced Hodgkin’s disease with MOPP, ABVD, or MOPP alternating with ABVD. New Engl J Med 327(21):1478–1484 11. Geel JA, Chirwa TC, Rowe B, Eyal KC, Omar F, Stones DK et al (2017) Treatment outcomes of children with Hodgkin lymphoma between 2000 and 2010: First report by the South African Children’s Cancer Study Group. Pediatr Blood Cancer 64:10 12. Myrehaug S, Pintilie M, Tsang R, Mackenzie R, Crump M, Chen Z et al (2008) Cardiac morbidity following modern treatment for Hodgkin lymphoma: supra-additive cardiotoxicity of doxorubicin and radiation therapy. Leukemia Lymphoma 49(8):1486–1493 13. Evens AM, Hong F, Gordon LI, Fisher RI, Bartlett NL, Connors JM et al (2013) The efficacy and tolerability of adriamycin, bleomycin, vinblastine, dacarbazine and Stanford V in older Hodgkin lymphoma patients: a comprehensive analysis from the North American intergroup trial E2496. Brit J Haematol 161(1):76–86 14. Canellos GP, Niedzwiecki D (2002) Long-term follow-up of Hodgkin’s disease trial. New Engl J Med 346(18):1417–1418 15. Sieber M, Tesch H, Pfistner B, Rueffer U, Paulus U, Munker R et al (2004) Treatment of advanced Hodgkin’s disease with COPP/ABV/IMEP versus COPP/ABVD and consolidating radiotherapy: final results of the German Hodgkin’s Lymphoma Study Group HD6 trial. Ann Oncol 15(2):276–282 16. Gobbi PG, Levis A, Chisesi T, Broglia C, Vitolo U, Stelitano C et al (2005) ABVD versus modified Stanford V versus MOPPEBVCAD with optional and limited radiotherapy in intermediate- and advanced- stage Hodgkin’s lymphoma: final results of a multicenter randomized trial by the Intergruppo Italiano Linfomi. J Clin Oncol 23(36):9198–9207 A. Fosså et al. 17. Johnson PW, Radford JA, Cullen MH, Sydes MR, Walewski J, Jack AS et al (2005) Comparison of ABVD and alternating or hybrid multidrug regimens for the treatment of advanced Hodgkin’s lymphoma: results of the United Kingdom Lymphoma Group LY09 Trial (ISRCTN97144519). J Clin Oncol 23(36):9208–9218 18. Radford JA, Rohatiner AZ, Ryder WD, Deakin DP, Barbui T, Lucie NP et al (2002) ChlVPP/EVA hybrid versus the weekly VAPEC-B regimen for previously untreated Hodgkin’s disease. J Clin Oncol 20(13):2988–2994 19. Hoskin PJ, Lowry L, Horwich A, Jack A, Mead B, Hancock BW et al (2009) Randomized comparison of the Stanford V regimen and ABVD in the treatment of advanced Hodgkin’s Lymphoma: United Kingdom National Cancer Research Institute Lymphoma Group Study ISRCTN 64141244. J Clin Oncol 27(32):5390–5396 20. Diehl V, Franklin J, Pfreundschuh M, Lathan B, Paulus U, Hasenclever D et al (2003) Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin’s disease. New Engl J Med 348(24):2386–2395 21. Borchmann P, Haverkamp H, Diehl V, Cerny T, Markova J, Ho AD et al (2011) Eight cycles of escalated- dose BEACOPP compared with four cycles of escalated-dose BEACOPP followed by four cycles of baseline-dose BEACOPP with or without radiotherapy in patients with advanced-stage Hodgkin’s lymphoma: final analysis of the HD12 trial of the German Hodgkin Study Group. J Clin Oncol 29(32):4234–4242 22. Engert A, Haverkamp H, Kobe C, Markova J, Renner C, Ho A et al (2012) Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin’s lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial. Lancet 379(9828):1791–1799 23. Hasenclever D, Loeffler M, Diehl V (1996) Rationale for dose escalation of first line conventional chemotherapy in advanced Hodgkin’s disease. German Hodgkin’s Lymphoma Study Group. Ann Oncol 7(Suppl 4):95–98 24. Tesch H, Diehl V, Lathan B, Hasenclever D, Sieber M, Ruffer U et al (1998) Moderate dose escalation for advanced stage Hodgkin’s disease using the bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone scheme and adjuvant radiotherapy: a study of the German Hodgkin’s Lymphoma Study Group. Blood 92(12):4560–4567 25. Engert A, Diehl V, Franklin J, Lohri A, Dörken B, Ludwig W-D et al (2009) Escalated-Dose BEACOPP in the treatment of patients with advanced-stage Hodgkin’s lymphoma: 10 years of follow-up of the GHSG HD9 study. J Clin Oncol 27(27):4548–4554 26. von Tresckow B, Kreissl S, Goergen H, Brockelmann PJ, Pabst T, Fridrik M et al (2018) Intensive treatment strategies in advanced-stage Hodgkin’s lymphoma (HD9 and HD12): analysis of long-term 13 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. Treatment of Advanced-Stage Hodgkin Lymphoma survival in two randomised trials. Lancet Haematol 5(10):e462–ee73 Kobe C, Dietlein M, Franklin J, Markova J, Lohri A, Amthauer H et al (2008) Positron emission tomography has a high negative predictive value for progression or early relapse for patients with residual disease after first-line chemotherapy in advanced- stage Hodgkin lymphoma. Blood 112(10):3989–3994 Behringer K, Mueller H, Goergen H, Thielen I, Eibl AD, Stumpf V et al (2013) Gonadal function and fertility in survivors after Hodgkin lymphoma treatment within the German Hodgkin Study Group HD13 to HD15 trials. J Clin Oncol 31(2):231–239 Federico M, Luminari S, Iannitto E, Polimeno G, Marcheselli L, Montanini A et al (2009) ABVD compared with BEACOPP compared with CEC for the initial treatment of patients with advanced Hodgkin’s lymphoma: results from the HD2000 Gruppo Italiano per lo Studio dei Linfomi Trial. J Clin Oncol 27(5):805–811 Viviani S, Zinzani PL, Rambaldi A, Brusamolino E, Levis A, Bonfante V et al (2011) ABVD versus BEACOPP for Hodgkin’s lymphoma when high-dose salvage is planned. New Engl J Med 365(3):203–212 Carde P, Karrasch M, Fortpied C, Brice P, Khaled H, Casasnovas O et al (2016) Eight cycles of ABVD versus four cycles of BEACOPP escalated plus four cycles of BEACOPP baseline in stage III to IV, International prognostic score >/= 3, high-risk Hodgkin lymphoma: first results of the phase III EORTC 20012 intergroup trial. J Clin Oncol 34(17):2028–2036 Mounier N, Brice P, Bologna S, Briere J, Gaillard I, Heczko M et al (2014) ABVD (8 cycles) versus BEACOPP (4 escalated cycles >/= 4 baseline): final results in stage III–IV low-risk Hodgkin lymphoma (IPS 0-2) of the LYSA H34 randomized trial. Ann Oncol 25(8):1622–1628 Merli F, Luminari S, Gobbi PG, Cascavilla N, Mammi C, Ilariucci F et al (2016) Long-term results of the HD2000 trial comparing ABVD versus BEACOPP versus COPP-EBV-CAD in untreated patients with advanced Hodgkin lymphoma: a study by Fondazione Italiana Linfomi. J Clin Oncol 34(11):1175–1181 Skoetz N, Trelle S, Rancea M, Haverkamp H, Diehl V, Engert A et al (2013) Effect of initial treatment strategy on survival of patients with advanced-stage Hodgkin’s lymphoma: a systematic review and network meta-analysis. Lancet Oncol 14(10):943–952 Skoetz N, Will A, Monsef I, Brillant C, Engert A, von Tresckow B (2017) Comparison of first-line chemotherapy including escalated BEACOPP versus chemotherapy including ABVD for people with early unfavourable or advanced stage Hodgkin lymphoma. Cochr Datab Syst Rev 5:CD007941. https:// doi.org/10.1002/14651858 Hasenclever D, Diehl V (1998) A prognostic score for advanced Hodgkin’s disease. International Prognostic Factors Project on Advanced Hodgkin’s Disease. New Engl J Med 339(21):1506–1514 Gallamini A, Hutchings M, Rigacci L, Specht L, Merli F, Hansen M et al (2007) Early interim 2-[18F]fluoro- 2- deoxy-D-glucose positron emission tomography 263 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. is prognostically superior to international prognostic score in advanced-stage Hodgkin’s lymphoma: a report from a joint Italian-Danish study. J Clin Oncol 25(24):3746–3752 Meignan M, Gallamini A, Meignan M, Gallamini A, Haioun C (2009) Report on the First International Workshop on Interim-PET-Scan in Lymphoma. Leukemia Lymphoma 50(8):1257–1260 Johnson P, Federico M, Kirkwood A, Fossa A, Berkahn L, Carella A et al (2016) Adapted treatment guided by interim PET-CT scan in advanced Hodgkin’s Lymphoma. New Engl J Med 374(25):2419–2429 Gallamini A, Tarella C, Viviani S, Rossi A, Patti C, Mule A et al (2018) Early chemotherapy intensification with escalated BEACOPP in patients with advanced-stage Hodgkin lymphoma with a positive interim positron emission tomography/computed tomography scan after two ABVD cycles: long-term results of the GITIL/FIL HD 0607 trial. J Clin Oncol 36(5):454–462 Borchmann P, Goergen H, Kobe C, Lohri A, Greil R, Eichenauer DA et al (2018) PET-guided treatment in patients with advanced-stage Hodgkin’s lymphoma (HD18): final results of an open-label, international, randomised phase 3 trial by the German Hodgkin Study Group. Lancet 390(10114):2790–2802 Press OW, Li H, Schoder H, Straus DJ, Moskowitz CH, LeBlanc M et al (2016) US intergroup trial of response-adapted therapy for stage III to IV Hodgkin lymphoma using early interim fluorodeoxyglucose- positron emission tomography imaging: Southwest Oncology Group S0816. J Clin Oncol 34(17):2020–2027 Zinzani PL, Broccoli A, Gioia DM, Castagnoli A, Ciccone G, Evangelista A et al (2016) Interim positron emission tomography response-adapted therapy in advanced-stage Hodgkin lymphoma: final results of the phase II part of the HD0801 Study. J Clin Oncol 34(12):1376–1385 Kobe C, Goergen H, Baues C, Kuhnert G, Voltin CA, Zijlstra J et al (2018) Outcome-based interpretation of early interim PET in advanced-stage Hodgkin lymphoma. Blood 132(21):2273–2279. https://doi. org/10.1182/blood-2018-05-852129 Casasnovas RO, Brice P, Lazarovici J, Ghesquieres H, Stamatoullas A, Dupuis J et al (2019) PET-adapted treatment of patients with advanced Hodgkin lymphoma (AHL2011): final results of a randomised, multi-centre, phase 3 study. Lancet 20(2):202–215 Biggi A, Gallamini A, Chauvie S, Hutchings M, Kostakoglu L, Gregianin M et al (2013) International validation study for interim PET in ABVD-treated, advanced-stage Hodgkin lymphoma: interpretation criteria and concordance rate among reviewers. J Nucl Med 54(5):683–690 Borchmann P, Haverkamp H, Lohri A, Mey U, Kreissl S, Greil R et al (2017) Progression-free survival of early interim PET-positive patients with advanced stage Hodgkin’s lymphoma treated with BEACOPP escalated alone or in combination with rituximab (HD18): an open-label, international, randomised A. Fosså et al. 264 48. 49. 50. 51. 52. 53. 54. phase 3 study by the German Hodgkin Study Group. Lancet Oncol 18(4):454–463 Younes A, Gopal AK, Smith SE, Ansell SM, Rosenblatt JD, Savage KJ et al (2012) Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol 30(18):2183–2189 Younes A, Connors JM, Park SI, Fanale M, O’Meara MM, Hunder NN et al (2013) Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin’s lymphoma: a phase 1, open-label, dose-escalation study. Lancet Oncol 14(13):1348–1356 Connors JM, Ansell SM, Fanale M, Park SI, Younes A (2017) Five-year follow-up of brentuximab vedotin combined with ABVD or AVD for advanced-stage classical Hodgkin lymphoma. Blood 130(11):1375–1377 Connors JM, Jurczak W, Straus DJ, Ansell SM, Kim WS, Gallamini A et al (2018) Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin’s Lymphoma. New Eng J Med 378(4):331–344 Chen RW, Gallamini A, Connors JM, Savage KJ, Collins GP, Grigg A et al (2018) Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin lymphoma (HL): Impact of cycle 2 PET result on modified progression-free survival (mPFS). J Clin Oncol 36:abstr 7539 Eichenauer DA, Plutschow A, Kreissl S, Sokler M, Hellmuth JC, Meissner J et al (2017) Incorporation of brentuximab vedotin into first-line treatment of advanced classical Hodgkin’s lymphoma: final analysis of a phase 2 randomised trial by the German Hodgkin Study Group. Lancet Oncol 18(12):1680–1687 Roemer MG, Advani RH, Ligon AH, Natkunam Y, Redd RA, Homer H et al (2016) PD-L1 and 55. 56. 57. 58. 59. 60. PD-L2 genetic alterations define classical Hodgkin lymphoma and predict outcome. J Clin Oncol. 34(23):2690–2697 Ramchandren R, Domingo-Domènech E, Rueda A, Trněný M, Feldman TA, Lee HJ et al (2019) Nivolumab for newly diagnosed advanced-stage classic Hodgkin lymphoma: safety and efficacy in the phase II checkmate 205 study. J Clin Oncol 37(23):1997–2007. https://doi.org/10.1200/ JCO.19.00315. PMID: 31112476 Loeffler M, Brosteanu O, Hasenclever D, Sextro M, Assouline D, Bartolucci AA et al (1998) Meta- analysis of chemotherapy versus combined modality treatment trials in Hodgkin’s disease. International Database on Hodgkin’s Disease Overview Study Group. J Clin Oncol 16(3):818–829 Andrieu JM, Yilmaz U, Colonna P, Loeffler M, Brosteanu O, Hasenclever D (1999) MOPP versus ABVD and low-dose versus high-dose irradiation in Hodgkin’s disease at intermediate and advanced stages: analysis of a meta-analysis by clinicians. J Clin Oncol 17(2):730–732 Aleman BM, Raemaekers JM, Tirelli U, Bortolus R, van’t Veer MB, Lybeert ML et al (2003) Involved- field radiotherapy for advanced Hodgkin’s lymphoma. New Engl J Med 348(24):2396–2406 Ferme C, Mounier N, Casasnovas O, Brice P, Divine M, Sonet A et al (2006) Long-term results and competing risk analysis of the H89 trial in patients with advanced-stage Hodgkin lymphoma: a study by the Groupe d'Etude des Lymphomes de l'Adulte (GELA). Blood 107(12):4636–4642 Kriz J, Reinartz G, Dietlein M, Kobe C, Kuhnert G, Haverkamp H et al (2015) Relapse analysis of irradiated patients within the HD15 trial of the German Hodgkin Study Group. Int J Radiat Oncol 92(1): 46–53 Optimizing Decision Making in Hodgkin Lymphoma 14 Susan K. Parsons, Joshua T. Cohen, and Andrew M. Evens Contents 14.1 Treatment Choices and Individualized Care 265 14.2 Treatment-Related Late Effects and Associated Human Cost 266 14.3 Risk, Impact, and Variability of Treatment-Related Late Effects 266 14.4 aucity of Harmonized Data to Guide Providers and Patients P Towards Individualized Treatment Choices 266 14.5 Disease Classification and Prognostication 267 14.6 14.6.1 14.6.2 Simulation Modeling Low-Dose CT Scan for Lung Cancer Diffuse Large B-Cell Lymphoma (DLBCL) 268 268 269 14.7 Decision Models in Hodgkin Lymphoma (HL) 270 14.8 Conclusion 271 References 272 14.1 S. K. Parsons (*) Tufts Medical Center, Center for Health Solutions, ICRHPS, Boston, MA, USA e-mail: sparsons@tuftsmedicalcenter.org J. T. Cohen Tufts Medical Center, Center for the Evaluation of Value and Risk in Health, ICRHPS, Boston, MA, USA e-mail: jcohen@tuftsmedicalcenter.org A. M. Evens Rutgers Robert Wood Johnson Medical School, RWJBarnabas Health, New Brunswick, NJ, USA Treatment Choices and Individualized Care Hodgkin lymphoma (HL) is one of the best curable cancers, particularly when presenting as early-stage disease [1–3]. Although outcomes differ by age, cure rates exceed 80–85% across most stages and ages. Despite these overall excellent outcomes, there is no clear consensus regarding treatment recommendations across age groups, and individual patients, with regard to several treatment options, including which chemotherapy regimen to use, the optimal number of chemotherapy cycles, and the role of sequential adjunctive radiation therapy (RT) [1, 2, 4–13]. Furthermore, choices and debate over therapeutic © Springer Nature Switzerland AG 2020 A. Engert, A. Younes (eds.), Hodgkin Lymphoma, Hematologic Malignancies, https://doi.org/10.1007/978-3-030-32482-7_14 265 S. K. Parsons et al. 266 options have further expanded to include if and how to integrate and use early/interim positron emission tomography (PET) therapy to guide treatment (i.e., response-adapted therapy), as well as the optimum integration of novel therapeutics into frontline therapy [6, 14–17]. 14.2 Treatment-Related Late Effects and Associated Human Cost Critically, because the majority of newly diagnosed HL patients are young (median age 35 years) [18], curing disease can come at considerable “human cost,” including treatment-related toxicities and late effects (LE) (e.g., secondary malignant neoplasms [SMN], cardiovascular disease [CVD]) and potential loss of young lives. The incidence of CVD and SMN rises exponentially >20–30 years after treatment. Results from analyses led by Dutch investigators and others have shown that the risk of SMNs do not appear to differ or be significantly lower over consecutive time periods [19–21]. Both Ng et al. [15] and Castellino et al. [18] have highlighted increased mortality among long-term HL survivors, although both of these studies reflect the impact of historical treatment approaches, including extended field radiotherapy. Additionally, cost-per-death analyses also have shown that HL has the second highest cost per death or lost productivity cost, behind only malignant melanoma [22]. Further, productivity analyses of cancer mortality have shown HL to be the second most costly cancer in terms of lost lifetime earnings [23]. In addition to economic consequences, HL survivors also experience significantly compromised health-related quality of life (HRQL) due to LEs [24]. 14.3 isk, Impact, and Variability R of Treatment-Related Late Effects The risk of SMN depends on many clinical factors (e.g., age at exposure, sex, stage) as well as several treatment-related factors (e.g., chemotherapy [type and number of cycles] and RT [dose and field]). A recent Dutch analysis highlighted the impact of radiation dose and field, sex, and smoking on the risk of breast, lung, and other cancers [19]. Studies have investigated the impact of age and sex on the development of solid cancers after treatment for HL [25] and the impact of sex and type of treatment (i.e., anthracycline chemotherapy ± radiation) on the incidence of major cardiac disease [26, 27]. However, it is not possible to use current population-level findings to reliably predict outcomes of alternative therapies for specific, individual patients and hence contribute to fully informed decision-making. 14.4 aucity of Harmonized Data P to Guide Providers and Patients Towards Individualized Treatment Choices Helping clinicians assess and navigate alternative HL treatment options for individual patients poses substantial challenges. First, ideal information is not available. Often, empirical data for contemporary therapies is limited to relatively short-term follow-up with differences in initial risk and response criteria driving therapy and limited information about the risk and severity of treatment-related LEs. While followup data from previous treatment eras offer insights [28], treatment changes and improvements over time limit the relevance of existing information. Second, the benefits and risks of different therapies depend in part on individual characteristics, such as patient age and sex, among other factors. A recent HL position paper by Travis and Ng et al. recommended development of c omprehensive risk prediction models for LEs to customize treatment strategies [29]. There is a need to harmonize individual patient data across age groups from recent trials and existing datasets while establishing a data repository that facilitates incorporation of future data. The past 15 years have seen publications of several clinical trials involving many pediatric and adult HL patients with early-stage and advancedstage disease [3, 30]. However, each study exam- 14 Optimizing Decision Making in Hodgkin Lymphoma ined a slightly different HL question and most used different treatments. The result was a range of distinct findings and hence a wide range of therapeutic choices (Table 14.1). Over the past 10 years, most HL studies worldwide have integrated PET-response- adapted designs, an approach that directs the type and/or amount of therapy based on PET scan results (positive vs. negative) early during the patient’s treatment course, usually after two chemotherapy cycles [16, 33]. These PET-response-adapted data have significantly expanded the range of treatments that providers and patients must consider in assessing treatment options for individual HL patients. Taken together, there remains a multitude of unanswered questions, especially for individual HL patients, as exemplified by the index case example above, including: (1) What is the efficacy of alternative treatments, and how do individual patient and disease characteristics influence efficacy? (2) What is the HRQL impact of each treatment option? (3) What are the incidence and severity of LEs (absolute risk for different SMNs and/or CVD), and how do these outcomes depend on treatment, individual patient characteristics, and disease characterisTable 14.1 HL case example A 29-year-old female presents with increasing size and number of lymph nodes and fatigue. Biopsy shows nodular sclerosis HL. PET staging shows non-bulky disease in right neck/supraclavicular, right hilum, and bilateral axillary (i.e., stage IIA unfavorable). Past family history includes father with myocardial infarction at age 50. Based on HL clinical study results, multiple valid alternative treatment options exist for this common case presentation, including: – ABVD × 4–6 cycles (dependent on CT response) without RT (NCI-C) [4, 5] – ABVD × 3 with PET-based decision on RT (i.e., none for CR) (RAPID) [6] – ABVD × 4 cycles + RT based on PET (with escalation to escalated BEACOPP for PET-2 positivity) (EORTC H10) [14, 15] – 2 ABVD + 2 escalated BEACOPP + RT (GHSG HD14) [15] – ABVD × 2 with PET-2 and then ABVD × 2 (PET negative) and BEACOPP × 2 (PET positive) CALGB 50604 [31] – 2 ABVD with PET-2 and then AVD × 6 (PET negative) or BEACOPP × 6 (PET positive) RATHL [32] 267 tics? (4) How does “real-world” HL data inform treatment decisions in light of patient preferences? 14.5 Disease Classification and Prognostication In adults, “early-stage” HL is often subdivided into two categories designated “favorable” and “unfavorable,” with the distinction made on the basis of clinical factors and blood test results [3]. However, there are several different classifications that have been developed and studied over the past 20 years in prospective HL clinical studies. The criteria used by the German Hodgkin Study Group (GHSG) and the European Organization for Research and Treatment of Cancer (EORTC) differ with regard to several factors, such as number of nodal groups. Furthermore, the “nodal maps” differ, reflecting differences between GHSG and EORTC clinical studies [14, 15, 34, 35]. In addition, clinical studies conducted in North America have utilized different criteria to delineate earlystage disease, and some HL clinical trials have not separated early-stage patients into different groups [4, 5]. These staging definition differences can influence the treatment patients receive and their outcomes. Advanced disease has generally been classified as Ann Arbor stage III and IV, but clinical trials have often included patients with high- risk stage II disease, such as those with B-symptoms, involvement at multiple sites, and/or bulky disease. The inclusion criteria have often varied on a study-by-study basis, leading to substantial patient heterogeneity across HL studies. Pediatric oncology research groups in the United States and across the world have used different criteria than adult groups use to categorize HL patients [10, 36]. While both pediatric and adult groups rely on the Ann Arbor classification system for staging, risk stratification has varied within these risk groups. For example, some adult studies classify patients with stage IIB disease with bulk as having early-stage disease, while pediatric trials currently designate patients as having advanced-stage disease based on inferior outcomes. Similarly, application of adult criteria would classify pediatric patients with stage IIIA disease as having advanced disease even though S. K. Parsons et al. 268 these patients have had superior outcomes compared to other pediatric subgroups (e.g., stage IIIB, IVA, IVB). Some pediatric trials do not include these patients in advanced-stage studies, but, rather, designate them to be at “intermediate” risk. Prognosis in adult advanced-stage HL as defined by the International Prognostic Index (IPS) in 1998 includes measurements of albumin, hemoglobin, sex, ages >45 years, stage IV, and the presence of leukocytosis or lymphocytosis [37]. HL patients with higher IPS scores had inferior treatment outcomes and were thus identified as potentially requiring more intensive therapy. The British Columbia Cancer Agency (BCCA) conducted an updated analysis of the IPS that showed that the utility of the IPS was altered [38]. In this analysis, the 5-year freedom from progression (FFP) ranged from 62% to 88% and 5-year OS ranged from 67% to 98% with a much narrower range of outcomes for patients ages <65 years (FFP ranging from 70% to 88% and 5-year OS ranging from 73% to 98%). Furthermore, in a multivariate regression analysis, which controlled for all IPS factors, only age and hemoglobin level retained independent significance. Notably, no new and more comprehensive prognostic models have been developed for HL (early stage or advanced stage) in more than 20 years. Because age is an integral component of the original IPS, attempts have been made to develop and validate a child-specific prognostic score, known as CHIPS (Childhood Hodgkin International Prognostic Score) [39]. The original testing found that several factors were independent predictors of event-free survival (EFS), including stage IV, large mediastinal mass, low albumin, and fever. Further validation in other cohorts of children and adolescents with advanced disease is underway. 14.6 Simulation Modeling Statistical and simulation modeling offers a rigorous approach to systematically and explicitly incorporate assumptions and information based on multiple data sources to explore how alternative treatments affect outcomes of interest, including LEs, survival, and quality-adjusted survival. Collectively, harmonization of independent patient data from large, international prospective studies and prominent cancer registries, along with development of common data standards, will establish robust “patient-specific” disease progression and LE probabilities that may be harnessed for dynamic decision-making tools with the expectation of ultimately improving outcomes across pediatric and adult HL. Decision models have proved useful in connection with other diseases when treatment options involve trade-offs, and the risks and benefits can vary substantially, depending on patient characteristics. Here, we review the models developed to evaluate measures to either help prevent or treat two conditions: (1) lung cancer and (2) diffuse large B-cell lymphoma (DLBCL). 14.6.1 L ow-Dose CT Scan for Lung Cancer The National Lung Screening Trial (NLST) demonstrated that for patients at high risk for lung cancer mortality, low-dose computed tomography (LDCT) reduces lung cancer mortality by 20 percent compared to screening by conventional chest X-ray [40]. Cost-effectiveness analysis revealed that compared to no screening, LDCT accrues 0.02 quality adjusted life years (QALYs) per person screened at an incremental cost of $1631 [41]. The corresponding cost-effectiveness ratio suggesting an outlay of $81,000 per QALY gained represents “good value” relative to contemporary benchmarks for the United States [42]. Nonetheless, there remains the possibility that more narrowly targeted selection of the population to be screened would accrue even greater benefits and, hence, achieve a more favorable cost-effectiveness ratio. Kovalchik et al. [43] reported that after ranking the NLST population by estimated lung cancer mortality risk, screening prevented one lung cancer death for every 5276 individuals in the lowest-risk quintile, but that it achieved the same benefit for every 161 screened among the highest-risk quintile. The risk function developed by Kovalchik et al. therefore offers an approach for reducing the amount of screening needed to achieve the same mortality reduction. Kumar et al. [44] investigated the efficiency of targeting individuals at even higher risk for lung cancer mortality than the NLST population as a 14 Optimizing Decision Making in Hodgkin Lymphoma whole. Using a different risk model than Kovalchik et al., Kumar et al. reported similar efficiency gains for reducing lung cancer mortality. Screening top decile individuals yielded a nearly eightfold gain in averted deaths per person screened, compared to screening of individuals in the bottom decile. Assessment using other outcome measures yielded less impressive efficiency gains. For life years gained, the benefit per person screened was 3.6 times greater for top mortality risk decile individuals, compared to the bottom decile. For quality-adjusted life year gains (QALYs), the corresponding ratio was 2.4. Finally, the cost-effectiveness of screening improved across the risk deciles by an even smaller relative margin, from $75,000 per QALY gained in the lowest-risk decile to $53,000 per QALY gained in the highest-risk decile, a ratio of approximately 1.4. The broad range of efficiency gains for different outcome measures illustrates both the strengths and limitations of risk targeting. When the targeting criterion—lung cancer mortality risk, in this case—matches the outcome measure, targeting vastly improves efficiency. On the other hand, when the outcome measure is less tightly related to the targeting measure, potential efficiency gains can decrease. Kumar et al. note, for example, that in the NLST cohort, higher-risk individuals were older, had greater smoking exposure, and were more likely to have a preexisting diagnosis of chronic obstructive pulmonary disease [44]. Because the characteristics making these individuals “high risk” also reduce life expectancy, targeting is less effective at maximizing life year gains. Likewise, mortality risk is inversely associated with future quality of life and positively associated with higher future care costs. Those factors further mitigate the efficiency gains from mortality risk targeting measured in terms of QALY gains and cost-effectiveness. 14.6.2 D iffuse Large B-Cell Lymphoma (DLBCL) Because there are multiple treatments for patients with DLBCL, and because treatments vary in terms of their intensity and side effects, an accurate prognosis is crucial to identifying a course of 269 care that appropriately accounts for a patient’s risks and benefits. In recent decades, clinicians have relied on the International Prognostic Index (IPI) to characterize risk [45]. The IPI produces a risk score ranging from 0 to 5 based on a series of dichotomized risk factors, including age (less than 60 vs. 60 or older), number of extranodal sites (0–1 vs. 2 or more), Ann Arbor stage (I or II vs. III or IV), lactate dehydrogenase levels (not elevated vs. elevated), and Eastern Cooperative Oncology Group performance status (2 or less vs. greater than 2). Incorporation of additional prognostic characteristics has improved the prognostic accuracy of the IPI, but limitations remain, including the dichotomous characterization of inputs and the tool’s semi-qualitative characterization of risk that does not specify probabilities for key outcomes such as mortality. To address these limitations, Biccler et al. [45] developed a model to predict overall survival and event-free survival as a function of both categorical characteristics (e.g., sex, Ann Arbor stage, presence or absence of B symptoms, among others) and continuous values (e.g., log leukocyte count, hemoglobin level, among others). The prediction reflects a weighted average of statistical models, with weights selected to maximize prediction accuracy. The authors have made the model available on the Internet (https://lymphomapredictor.org/). The results show overall survival (compared to background survival) and event-free survival, both of which are projected over a period of five years. Because this model incorporates finegrained individual characteristics and reports outcome probabilities over time, it represents a substantial improvement over earlier prognostic tools. Nonetheless, it has two key limitations. First, its projections are limited to a period of five years. That limitation reflects the extent of the follow-up in the population data used to build the model. Second, the model does not describe how alternative treatments influence outcomes. While clinicians and patients may infer that higher risks warrant more intensive treatment, the model does not quantify the resulting trade-offs. Altogether, trade-offs, in the form of adverse events and resource costs, are common. Typically, these downside impacts do not depend on the size S. K. Parsons et al. 270 of the potential benefit. The size of the potential benefit, and hence the magnitude of the net benefit, often depends on how big the baseline risk is. As a result, targeting individuals at highest risk for disease or severe outcomes often increases efficiency. The effectiveness of this strategy depends on the strength of the association between the risk stratification measure and the benefit measure. Prognostic risk models can help clinicians and patients weigh treatment alternatives, but these models can be limited by their time horizon and the extent to which they incorporate the impact of alternative therapies. 14.7 ecision Models in Hodgkin D Lymphoma (HL) Given the varying treatment approaches and their trade-offs relative to disease control and LE risks and the impact of individual patient characteristics, such as gender and age at the time of exposure, there has been considerable interest in the development of decision models for newly diagnosed HL. Our initial model of early-stage HL utilized published, group-level data from recent clinical trials to estimate simulated short-term and long-term outcomes [46]. We began with the development of a detailed disease map (Fig. 14.1), which highlights the health states through which a patient can move once diagnosed with HL. Based on best available information, we estimated the probability of transitioning from one health state to the next and the HRQL of each health state in the form of utility weights. To test the model, we created two hypothetical cases that differed with regard to gender, disease location, and extent of disease. We then compared the projected outcomes (life expectancy and QALYs) for each patient for each of two treatment modalities—chemotherapy alone and combined modality therapy [46]. Sensitivity analyses explored the impact on projected c linical outcomes of age at diagnosis and the assumed incidence and severity of late effects. The purpose of this initial model was not to identify which modality might be definitively superior to the other, but, rather, to illustrate that treatment recommendations should reflect patient factors, 4 B 5 Relapse 0.71 A Diagnosis & Treatment 9 C1 1 Cured With Relapse 0.74 C3 6 C2 Cured Without Relapse 0.80 At Risk 0.77 2 7 D Cured With Late Effects 0.67-0.73 Dead 0.0 10 8 3 Fig. 14.1 Utility Weight Simulation Model: The State Transition Diagram. The bubbles represent individual health states. The value within each bubble is the utility weight (or health-related quality of life impact) of that health state. The arrows represent transition pathways between states. Scaling each year of survival by that year’s utility weight (specified for each health state in the figure) and then summing the quality-adjusted years yields quality-adjusted survival 14 Optimizing Decision Making in Hodgkin Lymphoma Fig. 14.2 The State Transition Diagram— therapeutic-response enhanced model. Individuals in State A can proceed to States B or C2. The transition rates depend on whether the patient experiences a rapid or slow response to initial therapy—i.e., whether the individual progresses from substate A-i to A-ii, or to A-iii 271 B A-ii At-risk State “A” Relapse 0.71 1 RER C2 A-i 2 Preresponse data A-iii Cured Without Relapse 0.80 SER disease characteristics, and the outcome preferences of the patient and his/her provider. Decision models such as these can also be adapted as new information becomes available. For example, consider the use of early PET-based response. In the figure below, we have added the PET-adapted response as a new health state (that is, rapid early response or slow early response) (Fig. 14.2). Because addition of this new health state requires revision of the probabilities downstream, such as risk of relapse, the revised decision model can be run to estimate updated clinical outcomes. To extend this one step further, one could utilize this type of model as patients transition from one phase of care to another, namely, from active treatment to active surveillance or active surveillance to survivorship. By incorporating emerging information, patients and their providers can refine ongoing care needs and clarify areas of likely risk and uncertainty. The development of these types of dynamic decision models requires individual patient data from large numbers of patients to account for differences across patients in terms of their demographic characteristics and disease factors. Moreover, model development depends on identifying data projecting the impact of contemporary treatment on short- and long-term outcomes, including toxicity, death, relapse, and LEs. Data must also be updated, as additional information becomes available (e.g., from new trials, or from further follow-up of existing trials) and as new therapies are introduced. Critical to the implementation and dissemination of these tools is an understanding of how patients, caregivers, and providers would use such models in the real world, what concerns they have, what kind of decision support they need, and what outcomes they are interested in. As noted, our first version of the model estimated life expectancy and QALYs, but these outcomes can be modified to reflect what is salient and/or accessible to different stakeholders. 14.8 Conclusion Given the success of frontline treatments and the ability to salvage the majority of HL patients after disease progression or recurrence, the overall survival of HL is high. However, this survival comes at a cost to patients in the form of LEs, which can alter both the length and quality of survivorship. To reduce downstream LE risk, modifications have been made in frontline therapy, including: changes in indications for radiation, reduction in radiation dose and field among those S. K. Parsons et al. 272 receiving treatment, risk stratification to determine need for either dose reduction or dose escalation to optimize outcomes, and incorporation of novel agents, initially in the salvage setting and more recently in frontline therapy. Through data sharing and international collaboration, including across pediatric and adult specialties, we can create robust and nimble decision models to guide our patients and their families, alongside their providers, to enhance and optimize the difficult decisions that affect acute and long-term outcomes. 12. 13. 14. References 1. Giulino-Roth L et al (2015) Current approaches in the management of low risk Hodgkin lymphoma in children and adolescents. Br J Haematol 169(5):647–660 2. Armitage JO (2010) Early-stage Hodgkin’s lymphoma. N Engl J Med 363(7):653–662 3. Evens AM, Hutchings M, Diehl V (2008) Treatment of Hodgkin lymphoma: the past, present, and future. Nat Clin Pract Oncol 5(9):543–556 4. Meyer RM et al (2005) Randomized comparison of ABVD chemotherapy with a strategy that includes radiation therapy in patients with limited-stage Hodgkin’s lymphoma: National Cancer Institute of Canada Clinical Trials Group and the Eastern Cooperative Oncology Group. J Clin Oncol 23(21):4634–4642 5. Meyer RM et al (2012) ABVD alone versus radiationbased therapy in limited-stage Hodgkin’s lymphoma. N Engl J Med 366(5):399–408 6. Radford J et al (2015) Results of a trial of PET-directed therapy for early-stage Hodgkin’s lymphoma. N Engl J Med 372(17):1598–1607 7. Percival ME, Hoppe RT, Advani RH (2014) Bulky mediastinal classical Hodgkin lymphoma in young women. Oncology (Williston Park) 28(3):253-6–25860. C3 8. Crump M et al (2015) Evidence-based focused review of the role of radiation therapy in the treatment of early-stage Hodgkin lymphoma. Blood 125(11):1708–1716 9. Hay AE et al (2013) An individual patient-data comparison of combined modality therapy and ABVD alone for patients with limited-stage Hodgkin lymphoma. Ann Oncol 24(12):3065–3069 10. Wolden SL et al (2012) Long-term results of CCG 5942: a randomized comparison of chemotherapy with and without radiotherapy for children with Hodgkin’s lymphoma—a report from the Children’s Oncology Group. J Clin Oncol 30(26):3174–3180 11. Nachman JB et al (2002) Randomized comparison of low-dose involved-field radiotherapy and no radio- 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. therapy for children with Hodgkin’s disease who achieve a complete response to chemotherapy. J Clin Oncol 20(18):3765–3771 Straus DJ et al (2004) Results of a prospective randomized clinical trial of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by radiation therapy (RT) versus ABVD alone for stages I, II, and IIIA nonbulky Hodgkin disease. Blood 104(12):3483–3489 Laskar S et al (2004) Consolidation radiation after complete remission in Hodgkin’s disease following six cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapy: is there a need? J Clin Oncol 22(1):62–68 Raemaekers JM et al (2014) Omitting radiotherapy in early positron emission tomography-negative stage I/ II Hodgkin lymphoma is associated with an increased risk of early relapse: Clinical results of the preplanned interim analysis of the randomized EORTC/LYSA/ FIL H10 trial. J Clin Oncol 32(12):1188–1194 Andre MP et al (2017) Early positron emission tomography response-adapted treatment in stage I and II Hodgkin lymphoma: final results of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol 35(16):1786–1794. https://doi.org/10.1200/ JCO.2016.68.6394 Evens AM, Kostakoglu L (2014) The role of FDGPET in defining prognosis of Hodgkin lymphoma for early-stage disease. Blood 124(23):3356–3364 Olszewski AJ, Shrestha R, Castillo JJ (2015) Treatment selection and outcomes in early-stage classical Hodgkin lymphoma: analysis of the National Cancer Data Base. J Clin Oncol 33(6):625–633 Available from https://seer.cancer.gov/csr/1975_2015/. Schaapveld M et al (2015) Second cancer risk up to 40 after treatment for Hodgkin’s lymphoma. N Engl J Med 373(26):2499–2511 Aleman BM et al (2007) Late cardiotoxicity after treatment for Hodgkin lymphoma. Blood 109(5):1878–1886 van Leeuwen FE, Ng AK (2016) Long-term risk of second malignancy and cardiovascular disease after Hodgkin lymphoma treatment. Hematology Am Soc Hematol Educ Program 2016(1):323–330 Hanly P, Soerjomataram I, Sharp L (2015) Measuring the societal burden of cancer: the cost of lost productivity due to premature cancer-related mortality in Europe. Int J Cancer 136(4):E136–E145 Bradley CJ et al (2008) Productivity costs of cancer mortality in the United States: 2000–2020. J Natl Cancer Inst 100(24):1763–1770 Linendoll N et al (2016) Health-related quality of life in Hodgkin lymphoma: a systematic review. Health Qual Life Outcomes 14(1):114 Hodgson DC et al (2007) Long-term solid cancer risk among 5-year survivors of Hodgkin’s lymphoma. J Clin Oncol 25(12):1489–1497 Myrehaug S et al (2008) Cardiac morbidity following modern treatment for Hodgkin lymphoma: supra- 14 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. Optimizing Decision Making in Hodgkin Lymphoma additive cardiotoxicity of doxorubicin and radiation therapy. Leuk Lymphoma 49(8):1486–1493 Myrehaug S et al (2010) A population-based study of cardiac morbidity among Hodgkin lymphoma patients with preexisting heart disease. Blood 116(13):2237–2240 Castellino SM et al (2011) Morbidity and mortality in long-term survivors of Hodgkin lymphoma: a report from the Childhood Cancer Survivor Study. Blood 117(6):1806–1816 Travis LB et al (2012) Second malignant neoplasms and cardiovascular disease following radiotherapy. J Natl Cancer Inst 104(5):357–370 Diefenbach CS et al (2017) Hodgkin lymphoma: current status and clinical trial recommendations. J Natl Cancer Inst 109:4 Straus DJ et al (2018) CALGB 50604: risk-adapted treatment of nonbulky early-stage Hodgkin lymphoma based on interim PET. Blood 132(10):1013–1021 Johnson P et al (2016) Adapted treatment guided by interim PET-CT scan in advanced Hodgkin’s lymphoma. N Engl J Med 374(25):2419–2429 Coyle M, Kostakoglu L, Evens AM (2016) The evolving role of response-adapted PET imaging in Hodgkin lymphoma. Ther Adv Hematol 7(2):108–125 von Tresckow B et al (2012) Dose-intensification in early unfavorable Hodgkin’s lymphoma: final analysis of the German Hodgkin Study Group HD14 trial. J Clin Oncol 30(9):907–913 Engert A et al (2010) Reduced treatment intensity in patients with early-stage Hodgkin’s lymphoma. N Engl J Med 363(7):640–652 Keller FG et al (2018) Results of the AHOD0431 trial of response adapted therapy and a salvage strategy for limited stage, classical Hodgkin lymphoma: a report from the Children’s Oncology Group. Cancer 124(15):3210–3219 273 37. Hasenclever D, Diehl V (1998) A prognostic score for advanced Hodgkin’s disease. International Prognostic Factors Project on Advanced Hodgkin’s Disease. N Engl J Med 339(21):1506–1514 38. Moccia AA et al (2012) International Prognostic Score in advanced-stage Hodgkin’s lymphoma: altered utility in the modern era. J Clin Oncol 30(27):3383–3388 39. Schwartz CL et al (2017) Childhood Hodgkin International Prognostic Score (CHIPS) Predicts event-free survival in Hodgkin lymphoma: a report from the Children’s Oncology Group. Pediatr Blood Cancer 64:4 40. Aberle DR et al (2011) Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 365(5):395–409 41. Black WC et al (2014) Cost-effectiveness of CT screening in the National lung screening trial. N Engl J Med 371(19):1793–1802 42. Neumann PJ, Cohen JT, Weinstein MC (2014) Updating cost-effectiveness—the curious resilience of the $50,000-per-QALY threshold. N Engl J Med 371(9):796–797 43. Kovalchik SA et al (2013) Targeting of low-dose CT screening according to the risk of lung-cancer death. N Engl J Med 369(3):245–254 44. Kumar V et al (2018) Risk-targeted lung cancer screening: a cost-effectiveness analysis. Ann Intern Med 168(3):161–169 45. Biccler J et al (2018) Simplicity at the cost of predictive accuracy in diffuse large B-cell lymphoma: a critical assessment of the R-IPI, IPI, and NCCNIPI. Cancer Med 7(1):114–122 46. Parsons SK et al (2018) Early-stage Hodgkin lymphoma in the modern era: simulation modelling to delineate long-term patient outcomes. Br J Haematol 182(2):212–221 Part III Special Clinical Situations Pediatric Hodgkin Lymphoma 15 Georgina W. Hall, Cindy Schwartz, Stephen Daw, and Louis S. Constine Contents 15.1 15.1.1 15.1.2 15.1.2.1 15.1.2.2 15.1.2.3 15.1.2.4 15.1.3 15.1.4 15.1.4.1 15.1.4.2 15.1.4.3 15.1.4.4 15.1.4.5 15.1.4.6 15.1.4.7 15.1.5 15.1.5.1 15.1.5.2 15.1.5.3 15.1.5.4 15.1.6 Introduction Comparison of Pediatric/Adolescent Vs. Adult HL Classical Pediatric Hodgkin Lymphoma (PHL) Overall Strategies Low-Risk (Early Favorable) Disease Intermediate- and High-Risk (Advanced, Unfavorable) Disease Future Considerations in Classical Pediatric and Adolescent HL Nodular Lymphocyte-Predominant HL (NLPHL) Recurrence, Relapse, and Salvage in PHL Introduction Standard-Dose Salvage Chemotherapy Regimens Prognostic Factors at Relapse in Pediatric HL: Standard-Dose Chemoradiotherapy Vs. High-Dose Chemotherapy/Stem Cell Transplantation Role of Radiotherapy in Relapsed Hodgkin Lymphoma High-Dose Chemotherapy and Autologous Stem Cell Transplant High-Dose Chemotherapy and Allogeneic Stem Cell Transplantation Brentuximab Vedotin and Checkpoint Inhibitors Late Effects Cardiac Toxicities Pulmonary Toxicities Thyroid Toxicities Secondary Malignancies Summary/Future Directions References G. W. Hall (*) Pediatric and Adolescent Haematology/Oncology Unit, Children’s Hospital, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, Oxford, UK e-mail: georgina.hall@paediatrics.ox.ac.uk C. Schwartz Division of Pediatric Hematology Oncology and BMT, Medical College of WI, Milwaukee, WI, USA e-mail: cschwartz@mcw.edu 278 278 278 278 280 282 285 285 286 286 287 287 288 288 289 289 290 290 290 290 291 291 292 S. Daw Children and Young People’s Cancer Services, Division of Paediatrics, University College Hospital, London, UK e-mail: stephendaw@nhs.net L. S. Constine Department of Radiation Oncology and Pediatrics, University of Rochester Medical Center, Rochester, NY, USA e-mail: louis_constine@urmc.rochester.edu © Springer Nature Switzerland AG 2020 A. Engert, A. Younes (eds.), Hodgkin Lymphoma, Hematologic Malignancies, https://doi.org/10.1007/978-3-030-32482-7_15 277 G. W. Hall et al. 278 15.1 Introduction 15.1.1 Comparison of Pediatric/ Adolescent Vs. Adult HL Pediatric/young adult Hodgkin lymphoma (HL) is one of the few childhood malignancies that shares aspects of its biology and natural history with an adult cancer. Historically, children were thought to have a worse prognosis than adults due to antiquated treatment approaches that were initially designed to mitigate toxicities in children. It is now clear that effective therapy provides similar or even superior outcomes in children/ young adults. A comparison of the demographics of clinical presentations of pediatric/adolescent HL compared with adult HL is presented in Table 15.1. The first of the bimodal incidence peaks in HL occurs in teenagers and young adults (15–25-year age group). HL represents less than 5% of malignancies in children under the age of 15 years. In contrast, it represents 16–20% of malignancies in adolescents, making it the most common malignancy of this age group. Childhood HL is biologically indistinguishable from HL of young and middle-aged adults other than the relative incidence of specific disease histologies (Table 15.1). Mixed cellularity (MC) and nodular lymphocyte predominant (nLP) HL are the common types of HL in the preadolescent child; adolescents and young adults are most frequently (85%) afflicted with nodular sclerosing (NS) HL [3]. Only a third of children will have advanced disease; approximately 25% will have B symptoms. The incidence of HL with adverse features increases with age. Although there were no discernable differences in clinical presentation, response to therapy, or long-term outcome for adolescents (16–21 years) vs. young adults (22–45 years) treated similarly for HL [4], the treatment of children/adolescents and adults has diverged over the years primarily due to concerns about the late adverse effects of therapy. 15.1.2 C lassical Pediatric Hodgkin Lymphoma (PHL) 15.1.2.1 Overall Strategies The adverse consequences of therapy have driven the pediatric treatment paradigm of care. Clinical trials for pediatric and adolescent HL have been designed to both reduce long-term organ injury and increase efficacy. Pediatric oncologists responded first to developmental issues in the young child and later to the long- Table 15.1 Demographic and clinical characteristics at presentation of pediatric HL (modified from Refs. [1, 2]) Age range (years) Prevalence of HL cases (%) Gender Male/female Histology Nodular sclerosis (%) Mixed cellularity (%) Lymphocyte depleted (%) NLPHL (%) EBV associated Other risk factors Childhood HL ≤14 10–12 2–3:1 AYA HL 15–35 50 1:1–1.3:1 40–45 30–45 0–3 8–20 65–80 10–25 1–5 2–8 27–54% Risk factors: male, younger age, mixed cellularity histology, economically disadvantaged countries Lower SES increasing family size 20–25% Stage at presentation 30–35% with stage III or IV disease, 25% with B symptoms Relative survival rates at 5 years 94% (<20 years) Higher SES, smaller family size, early birth order 40% with stage III or IV disease, 30–40% with B symptoms 90% (<50 years) AYA adolescents and young adults, IPS International Prognostic Score, SES socioeconomic status Adult HL ≥35 34–40% 15 Pediatric Hodgkin Lymphoma 279 term treatment consequences in all young survivors in the design of treatment approaches. Recognition of musculoskeletal hypoplasia in young children with HL treated with high-dose radiation such as shortened sitting height, thin necks, and narrow shoulders and chest [5–8] precipitated the development of pediatric-specific regimens for HL. Combined- modality treatments, even for low-stage disease, allowed for the reduction of radiation dose [9] and field size, thus sparing normal structures (Fig. 15.1). This strategy for care was extended to older children and adolescents when hypothyroidism [11, 12], secondary cancers, and valvular and atherosclerotic heart disease [13, 14] were also found to be attributable to high-dose radiation. Low-dose radiation of 15–25 Gy has been the standard in childhood and adolescent HL for a b c Proportional Reduction in Mean Dose 1.2 Normalized mean dose decades. This reduced the potential for longterm risk without adversely impacting event-free survival. A convergence of treatment approaches for adults and children/adolescents may be emerging as recent adult trials have begun to address these issues and reduce radiation doses. With overall survival over 90%, the quality of survival becomes paramount. Early response to therapy was recognized [15, 16] as highly predictive of outcome. In Europe and the United States, response-based, risk- adapted approach to treating HL [17] allows therapy to be tailored to each individual, within the context of clinical trials. Dose-dense regimens [17] used are similar to those used by adult groups [18, 19], but the pediatric algorithms use the enhanced efficacy to support reduction of therapy. 1 0.8 Mantle 36Gy 0.6 IFRT 21Gy INRT 21Gy 0.4 0.2 0 Bilateral Breast Bilateral Lungs Heart Thyroid Organ Exposed Fig. 15.1 CT-based planning images depicting a historic mantle RT, compared to standard involved field radiation treatment (IFRT) and involved-node RT (INRT) for a patient with stage I disease involving the mediastinum. The postchemotherapy volume of initially involved paratracheal nodes is depicted in dark red and the cardiac silhouette is also evident. (a–c) Demonstration of the reduction in dose to breast, lung, heart, and thyroid for the female patient shown in (a) from Mantle 36Gy to IFRT 21Gy to INRT 21Gy. From Hodgson et al. [10] G. W. Hall et al. 280 Table 15.2 Risk groups employed by selected pediatric study groups [20] Study group Children’s Oncology Group [21, 22] EuroNet-PHL-C1, C2 [23] St. Jude/Stanford/ Dana-Farber Risk features (RF) Categorized as favorable or unfavorable risk by IPS Low risk IA/IIA no bulk/no LMA IA/Ba IIAa IA/IIA no bulk Intermediate/early unfavorable risk All others IIB, IIIA IVA IIA, IIB (no E), IIIA (no E) IA/IIA (RF), I IB IIIA IIII High risk IIIB, IVB IIEB IIIEA/ IIIB IV IIB, IIIB, IV. No bulk, ESR < 30 mm/h a 15.1.2.2 ow-Risk (Early Favorable) L Disease Although there have been differing definitions of low-risk disease (Table 15.2), risk-adapted approaches aim to define a cohort of patients that is curable with minimal therapy. Treatment group allocation, risk stratification, and response assessment vary according to each study group (Table 15.2), but all treatment groups define low risk based on stage and bulky disease. Children and adolescents with NLPHL are increasingly being treated with surgery alone or using low- dose regimens separate from those used for the treatment of classical HL. In the decade following the introduction of MOPP, secondary leukemia and sterility emerged as significant concerns [24–27]. During the 1980s, alkylator exposure and leukemia risk were reduced by alternating MOPP and ABVD [28, 29]. The goal was to avoid reaching thresholds of toxicity for any specific agent. The Pediatric Oncology Group (POG) compared four cycles of MOPP/ABVD plus 25.5 Gy to six cycles of chemotherapy alone without detecting differences in efficacy [15]. However, the profound sensitivity of the testes to procarbazine continued to cause sterility in boys, even with only two cycles of procarbazine-containing chemotherapy [30]. Although early attempts to avoid procarbazine were unsuccessful [31], more recent regimens have achieved this goal [17]. ABVD is used routinely in adults [32], but also has not been standard of care in children. Successful regimens have been devised by the German Paediatric Oncology Hodgkin’s Group (GPOH) [33] using OEPA (vincristine, etoposide, prednisone, and doxorubicin) in males (Table 15.3), by the French Society of Pediatric Oncology [36] using EBVP (etoposide, bleomycin, vincristine, prednisone), by Donaldson et al. [42] using VAMP (vincristine, doxorubicin, methotrexate, and prednisone), and by the Children’s Oncology Group (COG) using ABVE (doxorubicin, bleomycin, vincristine, etoposide) [43] and ABV-PC [41] all avoiding the use of procarbazine. With these approaches, EFS of 88–92% can be achieved without significant radiation or alkylator toxicity. Patients treated on these newer regimens receive less than 200 mg/m2 of doxorubicin plus or minus 20–25 Gy of involved-field radiation. The traditional approach of most pediatric HL treatment groups has been to use combined- modality therapy. Currently, these study groups are involved in evaluating methods to define low- risk patients who may be cured without radiotherapy, i.e., with chemotherapy alone. However, patients with early-stage HL treated with chemotherapy alone most frequently relapse in the initially involved lymph node(s) [44]. Therefore, an effort has also been made to reduce the radiation field size by including only the initially involved lymph node(s)—so-called involved node- radiation (INRT) [45]. The complexity of defining the field for INRT has led to the development of an alternative approach termed “involved-site radiation therapy” (ISRT) [46–48]. This is a modification of IFRT, recommended for patients who when optimal pre-chemotherapy imaging (PET-CT in a position similar to what will be used at the time of radiation therapy) is not available that would be necessary for INRT treatment planning. Because the delineation of the area of 15 Pediatric Hodgkin Lymphoma 281 Table 15.3 Treatment results for early, favorable pediatric HL Group or institution Combined- modality trials US CCG 5942 Patients (n) Stage Chemotherapy Radiation (Gy). field Survival (%) DFS, EFS, Follow-up or interval Overall RFS (years) 294 IA/B, IIA 4 COPP/ABV 21, IF 100 97 SFOP MDH-90 171 I − II 20, IF 97.5 91 27 I − II 78 5 GPOH-HD95 326,224 I, IIA IIB, IIIA 4 VBVP, good responders 4 VBVP 1–2 OPPA, poor responders 2 OEPA or 2 OPPA above + COPP 3 10 5 GPOH-HD2002 195,139 IA, 1B, IIA, IE, IIB,IIAE, IIIA 2 OEPA or 2 OPPA Above +2 COPP or 2 COPDAC Chemotherapy alone US CCG 5942 106 CS IA/B, IIA IA, IIA IA, IIA Response based RT AHOD0431 [D,E] St. Jude consortium[C] 278 88 20, IF References [34, 35] [36] CR: No RT PR: 20 IF (10–15 Gy boost) 20 ± 10–15 IF 99 97 94 88 5 [37, 38] 99.5 98.5 92 88 5 [39, 40] 4 COPP/ABV CR: None 100 91 3 [34] 4 AV-PC 4 VAMP 21 IF if PR 25.5 IF/ none if Early CR 99 100 80 89 4 5 [41] ABVD Adriamycin, bleomycin, vinblastine, and dacarbazine, AEIOP Italian Association of Hematology and Pediatric Oncology, CCG Children’s Cancer Group, ChlVPP chlorambucil, vinblastine, procarbazine, and prednisolone, COPP cyclophosphamide, vincristine (Oncovin), prednisone, and procarbazine, COPP/ABV cyclophosphamide, vincristine (Oncovin), procarbazine, prednisone, Adriamycin, bleomycin, and vinblastine, CR complete response, CS clinical stage, EF extended field, EFS event-free survival, HD Hodgkin’s disease, IF involved field, MDH multicenter trial, MH multicenter Hodgkin’s trial, MOPP nitrogen mustard, vincristine (Oncovin), procarbazine, and prednisone, M/T mediastinal/thoracic ratio, OEPA vincristine (Oncovin), etoposide, prednisone, and Adriamycin, OPA vincristine (Oncovin), prednisone, and Adriamycin, OPPA vincristine (Oncovin), procarbazine, prednisolone, and Adriamycin, PR partial response, PS pathologic stage, R regional, RFS relapse-free survival, RT radiotherapy, SFOP French Society of Pediatric Oncology, VAMP vinblastine, Adriamycin, methotrexate, and prednisone, VBVP vinblastine, bleomycin, etoposide (VP-16), and prednisone, AVPC doxorubicin, vincristine, prednisone, etoposide Mediastinal thoracic ratio < 0.33, lymph node <6 cm involvement is less precise, a somewhat larger treatment volume is treated than with INRT, but less than traditionally used with IFRT. Other radiation techniques that are contemporary and reduce the treatment volume include intensity-modulated radiation therapy, deep inspiration breath holding (to reduce the volumes of the lung and heart that might be exposed), and protons [49]. Nachman et al. showed an increased relapse rate in patients who did not receive radiation despite achieving CR at the end of chemotherapy [34, 35]. Late-response evaluation may not have identified the optimal cohort for reduction of radiation. Early response may better define the profoundly chemotherapy-sensitive patient who does not need radiation. Based on the 282 excellent outcomes of low-risk HL patients achieving CR after two cycles of chemotherapy [15], recent trials in the COG, the St. Jude/ DFCI/Stanford Consortium, and the EuroNet PHL group [50, 51], have examined early response to determine who does or does not require radiation post-chemotherapy. The prognostic importance of early chemotherapy response rather than end of chemotherapy response has led to the use of early response assessment (after 6–9 weeks) to titrate individual therapy and dose-dense regimens to maximize the early response rates. The St. Jude/DFCI/ Stanford Consortium has reported 2-year EFS of 90.8% in early-responding, low-risk patients with either classical or nodular lymphocytepredominant HL treated with 4 cycles of VAMP without radiation [51]. The most recent COG study (AHOD0431) found that early assessment by PET after one cycle is a predictor of recurrence [41, 52]. The current EuroNet PHL-C1 classical HL trial is evaluating PET activity after two intensive cycles of OEPA (cumulative dose of anthracycline is 160 mg/m2) to predict who does not require radiotherapy [53]. All such reductions in treatment may increase the risk of relapse; hence, adverse outcomes such as the need for high-dose salvage therapy (e.g., stem cell transplant or high-dose radiation) must be closely monitored. G. W. Hall et al. that eliminated traditional alkylating agents were not successful and resulted in a 70 and 49% 5-year EFS for stage III and IV HD, respectively [61]. It has been known for decades that outcome in HL is optimized by chemotherapeutic dose intensity. Only recently has this knowledge been considered a clue to improving outcome [62– 64]. ABVE-PC was developed by the COG (by adding prednisolone and cyclophosphamide to ABVE) for the treatment of advanced HL and dose density was increased by the use of 3-week cycles [17]. This regimen is similar to dose-dense regimens such as Stanford V and BEACOPP, developed simultaneously in the adult groups [18, 19]. BEACOPP and escalated BEACOPP are dose-intensive regimens with improved efficacy compared to COPP/ ABVD. Instead of further cumulative dose escalation, the COG and EuroNet PHL take advantage of dose-dense delivery to limit cumulative cytotoxic therapy. Such dose-intensive regimens also limit the cumulative dose of agents delivered to the early responders. The GPOH-HD/ EuroNet PHL group has substituted dacarbazine for procarbazine, resulting in excellent longterm results [40]. ABVE-PC is the backbone for all COG trials. This dose-dense approach allows for the elimination of procarbazine and the limitation of the doxorubicin and etoposide dose. The first such study (POG 9425) resulted in 5-year EFS of 84% and 15.1.2.3 Intermediate- and High-Risk 5-year overall survival (OS) of 95% for advanced (Advanced, Unfavorable) HL. Early responders (after three cycles of Disease ABVE-PC) on this study proceeded directly to For children with advanced-stage disease, receive 21 Gy regional RT. Others received two improving efficacy while limiting long-term tox- more cycles (total five ABVE-PC in 15 weeks) prior icity is even more challenging. The approach in to 21 Gy RT This backbone was used in AHOD0031 pediatric HL has been to increase the number of to evaluate a response-based vs. standard approach agents so as to limit cumulative doses of indi- to therapy for intermediate-risk disease and to study vidual agents. Regimens used in the 1980–1990s augmentation of therapy for high-risk patients with alternated MOPP/ABVD [29, 54] or used the a slow early response to therapy [65]. hybrid COPP/ABV [34] to avoid the cumulative Low-dose, involved-site radiation remains a doses of doxorubicin (300–400 mg/m2) and relevant modality of therapy in high-risk disease. bleomycin (120–160 mg/m2) associated with six The multicenter trial GPOH-HD95 used OPPA/ to eight cycles of the four-drug ABVD regimen COPP for girls and OEPA/COPP for boys with [28, 32]. radiation dose determined by end of chemotherMinimalistic dose regimens in combined- apy response. For the intermediate- and modality protocols, such as VEPA (Table 15.4), higher-risk groups (TG2 and TG4), outcome was 380 AHOD 0031 159 216 67 COG—P9425 (2009) Chemotherapy alone UKCCSG (2002) 68 99 St. Jude’s, Stanford, DFCI (2004) CCG 59704 145 77 CS IB/IIB or Bulky>6 cm CS III/IV CS IB, IIB, IIIA2, IIIB, IV IIA/IIIA1 “bulk” CS IV IIB, IIIB, IV III, IVB IIBE, IIIAE, IIIB, IV Not I/IIA no bulk, III, IVB 239 AHOD 0831 IIEB, IIIEA/B, IIIB, IVA/B 280 382 151 153 Stage Patients (n) Group of institution Combined-modality trials Germany, Austria HD-95 (2001) (2013) HD-2002 6–8 ChlVPP RER: 3 ABVE-PC SER: 5 ABVE-PC BEACOPP × 4 RER (F): BEACOPP × 4 RER (M): ABVD × 4 SER: BEACOPP × 4 6 VAMP/COP SER: Add Iifos/vinor × 2 RER: 5 ABVE-PC RER: ABVE-PC × 4 SER: ABVE-PC × 4 SER: ABVE-PC × 4 add DECA × 2 RER:ABVE-PC × 4 2 OEPA, 4 COPDAC 2 OEPA/OPPA + 4 COPP Chemotherapy Table 15.4 Treatment results for advanced, unfavorable pediatric Hodgkin lymphoma 84 55.2 5 Pediatric Hodgkin Lymphoma (continued) [59] [17] 80.8 5 21 IF Nonea 86 95 25.5 IF if PR 21 IF 5 93 [57] [56] [55] [40] [37] [38] [34] [35] [58] 76 5 3 10 21 GY 21 GY 15 IF if CR 94 80.2 84.3 75.2 79.3 87.9 87 84 Reference [16] 97 95.9 95.3 97.8 95 97 Follow-up interval (year) No 21 GY to residual or bulky disease 21GY IF RT No RT 21GY IF RT 21GY IF RT 21GY IF RT 20 ± 10–15 Gy IF RT PR:20–35, IF CR: No RT Radiation (Gy), field Survival, % DFS. EFS. or Overall RFS 15 283 CS IIB, III2A, IIIB, IV All except: IA, IIA non-bulk IIIB, IVB 81 1712 141 Stage CS I/IIb, CS IIB, CS III CS IV Patients (n) 394 COPP/ABV, CHOP, AraC/VP-16 4 MOPP/4 ABVD Standard arm; 21 IF/4 ABVE-PC Chemotherapy 6 COPP/ABV 81 79 85 94 96 98 None None Randomized: RER: ± RT SER: ± 2 DECA Radiation (Gy), field None Survival, % DFS. EFS. or Overall RFS 100 83 5 4 [60] 3 Follow-up interval (year) 3 [16] Reference [34] ABVD Adriamycin, bleomycin, vinblastine, and dacarbazine, ABVE-PC Adriamycin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide, AEIOP Italian Association of Hematology and Pediatric Oncology, AraC cytosine arabinoside, CAPTe cyclophosphamide, Adriamycin, prednisone, and teniposide, CCG Children’s Cancer Group, CCOPP vincristine (Oncovin), procarbazine, and prednisone, ChlVPP chlorambucil, vinblastine, procarbazine, and prednisolone, CHOP cyclophosphamide, hydroxydaunomycin, vincristine (Oncovin), and prednisone, COMP cyclophosphamide, vincristine (Oncovin), methotrexate, and prednisolone, COPP cyclophosphamide, vincristine (Oncovin), prednisone, and procarbazine, COPP/ABV cyclophosphamide, vincristine (Oncovin), procarbazine, prednisone, Adriamycin, bleomycin, and vinblastine, CR complete response, CS clinical stage, CVPP cyclophosphamide, vinblastine, procarbazine, and prednisone, DFS disease-free survival, EF extended field, EFS event-free survival, HD Hodgkin’s disease, IF involved field, MDH multicenter trial, MH multicenter Hodgkin’s trial, MOPP nitrogen mustard, vincristine (Oncovin), procarbazine, and prednisone, NR no response, OEPA vincristine (Oncovin), etoposide, prednisone, and Adriamycin, OPA vincristine (Oncovin), prednisone, and Adriamycin, OPPA vincristine (Oncovin), procarbazine, prednisolone, and Adriamycin, POG Pediatric Oncology Group, PR partial response, PS pathologic stage, R regional, RFS relapse-free survival, RT radiotherapy, SFOP French Society of Pediatric Oncology, TLI total lymphoid irradiation, UKCCSG United Kingdom Children’s Cancer Study Group, VAMP vinblastine, doxorubicin, methotrexate, and prednisone, VEEP vincristine, etoposide, epirubicin, and prednisolone, VEPA vinblastine, etoposide, prednisone, and Adriamycin, DECA dexamethasone, etoposide, cisplatin, cytarabine a Presence of adverse features = (t)hila, >4 nodal sites, bulk b 12 patients received 20–35 Gy, IF; 2 received whole lung irradiation US POG (1997) Response-based RT AHOD0031 (2010) Group of institution US CCG (2002) Table 15.4 (continued) 284 G. W. Hall et al. 15 Pediatric Hodgkin Lymphoma significantly better for those receiving radiation therapy (TG2, 0.78 vs. 0.92; TG 2 + 3, 0.79 vs. 0.91) [33, 38]. The Children’s Cancer Group also noted improved outcome for patients treated with radiation, despite CR at the end of chemotherapy [34, 35]. Kelly et al. [66] reported excellent results using a modified approach to BEACOPP that reduced doses of chemotherapy for girls and for boys with a rapid response. Nonetheless, this regimen is not being used currently because cumulative doses of chemotherapy remain high. Recent trials in both the COG and in Europe addressed early-response-directed approaches to limit the need for radiation. AHOD0031 for intermediate- risk HL used the dose-dense ABVE-PC regimen to support and evaluate the concept of an early-response-based algorithm [60]. This study showed that rapid early response (RER) could identify a cohort comprising 45% of patients who did not benefit from radiation. However, in a subset analysis from this study of patients with anemia and bulky limited-stage disease, the EFS was 89.3% for rapid early responder or complete remission patients who received IFRT, compared with 77.9% for patients who did not receive IFRT (P = 0.019) [67]. For patients who had a slow early response (SER), a marginal benefit from augmented chemotherapy was observed. The high-risk study (AHOD-0831) limited radiation fields for rapid early responders while augmenting therapy for slow early responders; outcomes were similar to POG9425 but used less radiation for RER and less doxorubicin for SER [E]. Adult patients with high risk randomized to ABVD vs. brentuximab with AVD have been reported to have a reduced risk of progression, death, or non-complete response [68], resulting in approval in the United States for this indication. However, it is not clear that this approach has an advantage in the setting of pediatric regimens that have had greater efficacy than ABVC. COG has a randomized, ongoing study comparing standard ABVE-PC to ABrVE-PC (Harker-Murray et al.), and the St. Jude Consortium is similarly evaluating the use of brentuximab with their backbone therapy. 285 15.1.2.4 Future Considerations in Classical Pediatric and Adolescent HL Progress has been made in the treatment of children with HL with all stages of disease and risk factors, but several issues remain to be resolved. Response to chemotherapy may define both the total amount of chemotherapy required and the need for radiotherapy (RT). For early-stage patients, the balance between chemotherapy dose and radiation exposure continues to be explored. Restriction of RT to initially involved lymph nodes (involved-node irradiation or involved-site irradiation) rather than chains (or regions) of nodes may affect the balance of risk. For high-risk disease, dose-dense chemotherapy improves efficacy and supports tailoring of therapy to the patient’s response. RT is clearly effective in enhancing the local control of PHL, but has a dose-dependent toxicity profile favoring a limited volume/dose approach. Ongoing studies are needed to assess the role of RT for initial bulky disease, to residual postchemotherapy disease (particularly if it is PET negative), and to involved organs. Carefully designed and sequential evidence-based studies are needed to continue to improve efficacy while limiting toxicity. 15.1.3 Nodular Lymphocyte- Predominant HL (NLPHL) An indolent, peripheral, NHL-like disease, NLPHL was recognized in the early 1990s as a clinicopathologically distinct form of HL [69]. Unlike classical HL, NLPHL is a CD20-positive, CD30- and CD15-negative, B cell lymphoma that is not associated with EBV genomic integration. There is a distinct male predominance (ratio 2–3:1) with nearly 90% of pediatric patients having early-stage disease (IA/IIA). A higher percentage (10–20%) of children have NLPHL [3] compared to adults (3–8%) [70], and although >50% of pediatric and adolescent cases are under the age of 14 years [71], the incidence peaks between 14 and 18 years. Peripheral lymphadenopathy is the most common presentation involving the axilla, cervical, and G. W. Hall et al. 286 inguinal regions, often present for months or years. Rarely is advanced or central disease seen. Adults with early-stage NLPHL are treated with involved-field radiotherapy, standard cHL therapy, or combined-modality therapy. Children have, until 2005 and the start of NLPHL-specific clinical trials, received standard pediatric cHL therapy with combined-modality chemoradiotherapy [72], which is excessively toxic. Morbidity, even mortality, secondary to repeated courses of intensive therapy to eradicate this indolent, usually nonfatal disease has resulted in a drive to reduce the intensity of therapy to avoid late effects [71]. Children with fully resected early-stage nLPHD have been cured without the need for any chemoradiotherapy [73–76], but the specific situations in which this strategy is appropriate are currently under investigation. Two nonrandomized clinical trials, EuroNetPHL-LP1 and COG’s AHOD03P1, have looked at reducing the toxicity of upfront therapy for early-stage disease (stage I and II) [73, 74]. As salvage therapy is effective for late or even multiple relapses which generally recur at the original site of disease with no stage upgrade, OS is expected to remain near to 100% [77]. The EuroNetPHL-LP1 used surgical resection alone or low-dose anthracycline-free CVP chemotherapy for non-resectable disease, and COG’s AHOD03P1 used AVPC (equivalent to CHOP) with selective radiotherapy. Excellent EFS rates of 60–75% with no or low-dose chemotherapy have been obtained and only 10% of COG patients received RT, maintaining 100% OS [78]. Because of transformation rates of approximately 5% to aggressive B-NHL [79] in adults, usually diffuse large B cell lymphoma [80], concerns regarding reduced therapy that could potentially allow persistence of the CD20 clone and increased transformation rates remain. In theory, the addition of rituximab would help to specifically eradicate the CD20 clone and reduce transformation rates. However, transformation rates in children are not known but appear extremely low. Rituximab has been studied in adults for use in this and all other CD20-positive lymphomas [81]. The pediatric community have traditionally been wary about using rituximab in young children because of impact on immune status/memory. As early-stage NLPHL is viewed as a highly curable disease with minimal chemotherapy or surgery alone, the use of rituximab has been reserved for treating more aggressive, advanced, or relapsed disease. Assessing the impact of adjuvant rituximab therapy on EFS and transformation rates in children within a randomized clinical trial has been the unattainable aim of clinicians for well over a decade. The reluctance of the pediatric community to use rituximab in this and other CD20+ lymphomas is abating. Current proposed clinical trials using low- dose NHL-like therapy including anti-CD20 therapy are focused on the natural history, establishing risk categories, variant histologies, and transformation rates, with biological substudies looking at specific molecular characteristics. 15.1.4 Recurrence, Relapse, and Salvage in PHL 15.1.4.1 Introduction Relapsed and refractory classical Hodgkin lymphoma (HL) remains a clinical and therapeutic challenge. Approximately 10% of patients with early-stage and up to 30% with advanced-stage disease relapse after first-line chemotherapy. Cure can still be achieved in a substantial proportion of patients with recurrent disease, but there is no uniform approach to salvage therapy. The optimal salvage treatment has not been defined in children and adolescents as there are no randomized trials defining the “best” salvage chemotherapy regimen or comparing standard-dose chemotherapy (SDCT) vs. high-dose chemotherapy and autologous stem cell transplant (HDCT/ ASCT), which is often considered the standard of care in adult practice. Pediatric practice adopts a more individualized risk-stratified and responseadapted approach to salvage treatment with both non-transplant (SDCT plus radiotherapy) and transplant (SDCT plus HDCT/ASCT) salvage. At the point of relapse, a full disease reassessment including histologic confirmation is mandatory and then an analysis of pre-salvage risk factors is undertaken. All patients have a common starting point with re-induction SDCT and this is followed by consolidation treatment. The choice of consolidation treatment is guided by 15 Pediatric Hodgkin Lymphoma risk stratification based on prognostic factors as well as an assessment of chemosensitivity which is commonly done after two cycles of SDCT and includes FDG-PET response. Achieving a complete metabolic remission on FDG-PET prior to consolidation has been shown to be highly prognostic in the relapse setting and is considered to be a major goal of re-induction SDCT [82]. Consolidation after SDCT will be radiotherapy only in “low-risk” relapse or HDCT/ASCT in “standard-risk” relapse, and these two strategies will be appropriate for the vast majority of relapse/progressive HL. A small number of patients are refractory to SDCT and do not achieve a CR with two or more lines of SDCT and these are “high-risk” patients [82]. Consolidation in these high-risk patients may be either conventional HDCT/ASCT possibly with post-HDCT consolidation RT or maintenance- targeted therapy such as brentuximab vedotin, or alternative experimental approaches may be applied including novel agents such as checkpoint inhibitors or allogeneic transplantation. 15.1.4.2 Standard-Dose Salvage Chemotherapy Regimens After recurrence is noted, the first step is reinduction with a SDCT salvage regimen. There is no “best” chemotherapy regimen at salvage, and there are no randomized studies comparing standard-dose chemotherapy regimens. The choice of regimen should take account of primary therapy, use of non-cross-resistant drugs, and cumulative drug toxicities. The aim of salvage therapy is to obtain cytoreduction and to demonstrate chemosensitivity which is done most accurately now with FDG-PET as firstline treatment. It also facilitates collection of peripheral stem cells for ASCT. Salvage regimes can be divided into intensive conventional regimens1 (mini-BEAM), cisplatinbased regimens2 (ESHAP, DHAP [ESHAP, DHAP, APPE, DECAL]), ifosfamide- based Mini-BEAM; BCNU, etoposide, cytarabine, melphalan ESHAP, etoposide, methylprednisolone, cytarabine, cisplatin; DHAP, dexamethasone, cytarabine, cisplatin; APPE, cytarabine, cisplatin, prednisone, etoposide; DECAL, cytarabine, cisplatin, prednisone, etoposide, asparaginase 1 2 287 regimens3(EPIC, IEP, ICE, IV), or others4 (GV, IGEV). The COG uses IV as its standard regimen because of efficacy and with the intent of avoiding etoposide-induced secondary malignancy after stem cell transplantation [83]. In Europe, alternating IEP/ABVD was used in the EuroNet-PHL-R1 trial but more recently the IGEV regimen has been widely adopted. The decision to continue salvage therapy with RT consolidation vs. HDCT/ASCT is based on assessment of predictive factors. 15.1.4.3 Prognostic Factors at Relapse in Pediatric HL: Standard-Dose Chemoradiotherapy Vs. High-Dose Chemotherapy/ Stem Cell Transplantation Prognostic factors at relapse may be used to allocate patients to a risk-stratified salvage approach. This is in contrast to adult practice where consolidation with HDCT/ASCT is considered standard of care. There are currently no universally accepted prognostic criteria in children (or adults) defining individualized salvage treatment plans. Factors which are prognostically important include time to relapse, prior treatment in first line, stage/disease burden at relapse, and response to salvage chemotherapy. In children, low-risk patients may be salvaged with RT consolidation only, while standard-risk patients are salvaged with HDCT. The cut point between low- and standard-risk patients is not universally defined. In Europe, low-risk patients salvaged with SDCT plus RT only include those with early relapse after up to 4 cycles of chemotherapy and late relapse after up to 6 cycles with all of the following: nodal relapse, no prior RT (or relapse only outside prior RT fields), consolidation RT that has acceptable toxicity (i.e., no excessive RT fields), and chemotherapy-responsive disease. All other patients have intensification with HDCT/ASCT. EPIC, etoposide, vincristine epirubicin, prednisolone; IEP, ifosfamide, etoposide, prednisolone; ICE, ifosfamide, carboplatin, etoposide; IV, ifosfamide, vinorelbine 4 GV gemcitabine, vinorelbine; IGEV, ifosfamide, gemcitabine, vinorelbine, prednisolone 3 G. W. Hall et al. 288 Time to relapse from end of first-line treatment is the most important pretreatment risk factor and highly significant for OS and EFS in pediatric studies [84–86] and dominated all other prognostic factors in multivariate analysis of the ST-HD-86 trial, the largest prospective pediatric relapse trial published to date [87], with DFS of 41, 55, and 86% for those with refractory disease, early relapse, and late relapse, respectively. This study showed that salvage can be risk adapted because subgroups with markedly better or worse prognosis can be defined. Stage IV and extranodal disease were also associated with lower OS. A recent French experience [88] found the only relevant prognostic factors to be time to relapse and chemoresistance with primary progressive HL having an EFS <40% compared with approximately 80% in late relapse and chemosensitivity (CR or PR >70%) to salvage associated with a DFS of 77% vs. 10% with poor response (p < 0.0001). Chemosensitivity to SDCT and disease status at transplantation are also predictive of outcome. In one study, 5-year FFS was 35% for patients with chemosensitive disease vs. 9% with chemoresistant disease [84]. Another group found 68% OS and 59% FFS at 5 years in chemosensitive patients vs. 18% and 0% in chemoresistant patients [85]. Several particularly adverse factors have been noted. Chemoresistant patients had 5-year FFS of 0% with HDCT/ASCT [85]. Adolescents with B symptoms at recurrence had poor OS even after HDCT/ASCT (11-year OS 27% with B symptoms vs. 60% without) [89]. No difference in OS or FFS between age subgroups or in comparison with adult cohorts has been reported by several studies [84, 85, 90]. Of note, many of these studies did not incorporate FDG-PET response assessment which is now well recognized as the most important prognostic factor, which may overcome the significance of some factors as is the case in first-line treatment [91]. 15.1.4.4 Role of Radiotherapy in Relapsed Hodgkin Lymphoma Radiotherapy has an important role in salvage, but must be individualized based on previous radiation exposure, in or out of field recurrence, stage at recurrence, and the toxicities of total treatment burden [92]. Increasing numbers of patients are RT naïve at relapse as the use of RT is increasingly restricted in first-line treatment and RT fields are also becoming highly restricted in some firstline trials to FDG-PET-positive residua. Therefore, at relapse many patients have never received RT, and some other patients may relapse in prior disease sites that have never received RT because they received focal targeted RT only. Salvage with RT alone is generally not recommended, but integration of RT in salvage is relevant in two contexts: 1. As consolidation treatment in low-risk group patients after SDCT. 2. In selected patients as consolidation after HDCT/ASCT 15.1.4.5 High-Dose Chemotherapy and Autologous Stem Cell Transplant COG protocols have studied HDCT/ASCT and immunomodulatory therapy in all patients except the lowest-risk group (late relapse without bulky disease or B symptom in those initially treated for IA/IIA disease with minimal systemic therapy) [93]. In Europe, HDCT/ ASCT has a recognized role in salvage for those with higher-risk features, namely, all primary progressive HL and early relapse after 6 cycles of first-line chemotherapy, all relapse with poor response to reinduction, and finally those patients in whom RT consolidation is either not feasible (advanced-stage relapse) or too toxic (extensive RT fields required or re-irradiation of prior irradiated sites). Patients without high-risk features and who achieve a complete FDG-PETdefined response after two cycles of SDCT may receive only consolidation SDCT plus RT. There are no studies that define the most effective HDCT. BEAM and CVB (cyclophosphamide, etoposide, carmustine) are commonly used. TBI-containing regimens confer no benefit and are associated with increased toxicity and late effects. Transplant-related mortality is down to 0–2% in some series. A higher TRM rate has been associated with history of atopy, thoracic irradiation, multiple chemotherapy regimens, and multiple relapses. 15 Pediatric Hodgkin Lymphoma Series with HDCT/ASCT in pediatric and adolescent patients are small and report EFS rates of 31–67% [84, 85, 90, 94]; outcome for children is similar to adults with HDCT/ASCT [84, 90]. Studies that evaluate survival benefit rather than event-free survival after disease recurrence often rely on transplant after second or later recurrence to achieve good OS [85, 95]. Patients with primary progressive disease and those resistant to salvage regimens remain a huge challenge. SDCT with radiotherapy will not afford a chance of cure, but even HDCT/ ASCT is inadequate therapy for most such patients. New approaches to such patients, such as use of post-HDCT consolidation maintenance-targeted treatment, were tested in the Aethera trial with up to 16 cycles of brentuximab vedotin or post-HDCT radiotherapy which is also an option to minimize further relapse. Allogeneic SCT or immunomodulatory therapy may prove beneficial [93]. Long-term follow-up is required post-HDCT for detection of late relapse and development of second cancers, which have been reported at a rate of 5–10% at 5 years and substantially higher at 20 years or more in some series. Thirty-eight percent of deaths occurred 4–12 years after ASCT; 85% of relapses occur within 2 years of ASCT [86]. 15.1.4.6 High-Dose Chemotherapy and Allogeneic Stem Cell Transplantation The role of allogeneic transplant in relapsed HL remains unknown. The poor outcome with HDCT/ASCT in chemotherapy poor responders to salvage and those who remain FDG-PET positive after salvage has resulted in exploration of alloSCT. Allogeneic transplantation is not recommended as the initial transplant approach outside of a clinical trial setting [96] due to the high non-relapse mortality (NRM) rate, mainly caused by graft vs. host disease and infection. Reduced intensity conditioning (RIC) ameliorates the NRM while maintaining theoretical graft vs. lymphoma effect. Allogeneic-SCT may be an option for relapse post-HDCT/ASCT and for patients with refractory advanced-stage HL and chemoresistant disease at salvage. 289 Children and adolescents allografted for HL had an OS of 45% and PFS of 30% at 5 years [97]. All were heavily pretreated, almost half with HDCT/ASCT. Those with chemosensitive disease and good performance status achieved 3-year OS of 83% and PFS of 60%. NRM was 21 ± 4% in both the RIC and myeloablative conditioning groups. RIC was associated with a significantly higher relapse risk compared to myeloablative conditioning. Graft vs. host disease did not affect relapse rate. Although studies based on registry data are useful, prospective trials are required to gain a better understanding of the role of allogeneic transplantation. The indications, optimal time point, conditioning regimen, and GVHD prophylaxis still need to be better defined. With the advent of newer immunotherapy agents, including checkpoint inhibitors, the role of alloSCT globally in HL is under review and the numbers of such transplants are declining globally. 15.1.4.7 Brentuximab Vedotin and Checkpoint Inhibitors In recent years there have been two early-phase pediatric trials investigating novel agents in children. The first is the phase I/II pediatric trial (ClinicalTrials.gov number NCT01492088) investigating single-agent brentuximab vedotin in R/R HL and anaplastic large cell lymphoma [98]. The recommended phase II dose was 1.8 mg/kg as in adults and the ORR was 47% (CR rate 33%, PR rate 12%) in HL patients and toxicity was manageable. This compares with the pivotal phase II study in adults where the ORR was 75% (CR rate 34%) [99]. The second is the ongoing risk-stratified and response-adapted phase II salvage trial in first R/R HL of nivolumab plus brentuximab vedotin followed by bendamustine plus brentuximab vedotin in poor initial responders in first R/R HL in children and young adults (Checkmate 744 trial, AHOD1721; NCT02927769) [100]. The preliminary results of this study are recently presented showing 64% of patients achieved a CMR after brentuximab vedotin plus nivolumab. Of those inadequate responders that switched to second-line brentuximab vedotin plus bendamustine, all achieved a CMR after 2 cycles of this intensification. 290 The overall CMR rate with either first or second salvage in this trial was 86%, demonstrating that only a small number of patients cannot achieve a CMR pre-HDCT with these combinations. Treatments that block the interaction between programmed death-1 (PD-1) and its ligands have shown high levels of activity in adults with HL. The anti-PD-1 antibody nivolumab induced objective responses in 20 of 23 adult patients (87%) with relapsed HL [101]. Another anti- PD- 1 antibody, pembrolizumab, produced an objective response rate of 65% in 31 heavily pretreated adult patients with Hodgkin lymphoma who relapsed after receiving brentuximab vedotin [102]. These agents may be used as a bridge to transplant, as post-HDCT maintenance brentuximab vedotin, or as alternatives to conventional SDCT. These novel agents when used as a single agent achieve CR rates of 19–33%, but in combination achieve higher CR rates as in the Checkmate trial [100]. An interesting combination is brentuximab vedotin plus bendamustine [103] which achieves CR rates in excess of 75% which means that most patients can achieve a CR prior to HDCT making the use of alloSCT which is often used in patients that cannot achieve a CR less appealing. 15.1.5 Late Effects Long-term adverse sequelae of greatest concern in children treated for HL (particularly with regimens including high-dose radiation) include impairment of muscle and bone development [5] and injury to the lungs [104], heart [105], thyroid gland [11, 12], and reproductive organs [106]. Cardiovascular dysfunction, pulmonary fibrosis, and secondary malignancies significantly compromise the quality and length of life in survivors [107]. 15.1.5.1 Cardiac Toxicities High-dose (>30 Gy) radiation to the mediastinum has been associated with significant long-term effects in patients with HL. Stanford investigators reported that the actuarial risk of developing cardiac disease necessitating pericardiectomy was 4% at 17 years in a series of long-term G. W. Hall et al. survivors of childhood HL who had received high-dose radiation [14]. Screening echocardiogram, exercise stress test, and resting and 24-h ECG identified numerous clinically significant cardiac abnormalities in HL patients who had mediastinal irradiation at a median age of 16.5 years (range, 6.4–25 years). Significant valvular defects were detected in 42%, autonomic dysfunction in 57%, persistent tachycardia in 31%, and reduced hemodynamic response to exercise in 27% of patients [108]. With the introduction of techniques that reduce the radiation dosage to the heart, rates of radiation-associated cardiac injury have declined dramatically. Mediastinal irradiation given for HL may further predispose patients with PHL to anthracycline-related myocardiopathy [14, 109]. Cardiac dysfunction after anthracycline therapy itself is notable, with the highest risk in those receiving high cumulative doses or in young children who may be affected by an adverse effect on cardiac myocyte growth [14, 109]. Fortunately, most pHL patients are adolescents and current pHL regimens doses are significantly lower than those used in adult ABVD regimens. 15.1.5.2 Pulmonary Toxicities Chronic pneumonitis and pulmonary fibrosis should be rare in the current era of treatment for primary HL (Fig. 15.1). Predisposing therapies include thoracic radiation and bleomycin chemotherapy [104, 105]. The bleomycin in ABVD can cause both acute pulmonary compromise and late pulmonary fibrosis and can be augmented by the fibrosis that can be associated with pulmonary radiation. Asymptomatic pulmonary dysfunction that improves over time has been observed after contemporary combinedmodality treatment. 15.1.5.3 Thyroid Toxicities Thyroid sequelae are common after RT for PHL. Hypothyroidism, hyperthyroidism, thyroid nodules, and thyroid cancer have been observed in long-term survivors [11, 12]. Of these, hypothyroidism, particularly compensated hypothyroidism, defined as thyroid-stimulating hormone (TSH) elevation in the presence of a normal thyroxine 15 Pediatric Hodgkin Lymphoma 291 (T4) level, is the most common thyroid abnormality. The primary risk factor for hypothyroidism is higher cumulative radiation dosage; the influence of age remains controversial [11, 12]. As many as 78% of patients treated with radiation dosages greater than 26 Gy demonstrate thyroid dysfunction, as indicated by elevated TSH levels [11]. 15.1.5.4 Secondary Malignancies The overall cumulative risk of developing a subsequent malignancy after treatment for PHL has been reported to range from 7% to 10% at 15 years from diagnosis and rises to 16–28% by 20 years (Table 15.5) [116]; these data are based on patients treated in earlier decades. The most common secondary malignancies historically included both secondary acute myeloid leukemia (MDS/secondary AML) and solid tumors. However, leukemias are now infrequent due to changes in chemotherapy. Female breast cancer is a particular concern but is likely to be less common with current radiation doses and techniques, since it is associated with RT fields that include breast tissue (especially mantle fields) and higher radiation doses (Fig. 15.1). 15.1.6 Summary/Future Directions Tremendous strides have been made in treating children with HL, both in terms of cure and reduction of toxicity. Devising new strategies to treat children with HL is problematic because of the overall success of current treatment regimens. However, grouping patients into different risk categories, using response-based therapy and newer imaging techniques, allows investigators to construct protocols intended to diminish therapy-induced toxicity for patients with favorable prognoses. These protocols also aim to improve efficacy of treatment for patients with intermediate and unfavorable prognoses. Unfortunately, the ability to conduct clinical trials, where the difference in survival between treatment arms is likely to be small, is compromised by the large patient numbers required to detect such differences. If a reduction in treatment toxicity is the intended goal of a new regimen, then many years of follow-up are necessary to prove efficacy. For patients with refractory, or multiple relapsed disease, phase II studies investigating the use of monoclonal anti-CD30 and anti-PD-1 antibodies alone and in combination, and with other checkpoint inhibitors, in children and adolescents are ongoing internationally. The importance of investigators working together throughout the world to share data and new treatment approaches in order to cure children with HL safely is clear. Acknowledgments Thanks to Laura Finger, Rochester, for her help with the final draft and references of the third edition 2019. Table 15.5 Secondary cancers after childhood HL Reference Stanford [110] Cohort size 694 LESG [111] 1641 [112] Roswell [113] LESG [114] US/European [115] University of Rochester/Johns Hopkins/University of Florida/ St. Jude/Dana-Farber [116] Number of Time period secondary cancers studied 1960–1995 59 1136 182 1380 5925 1940s to 1991 1955–1986 1960–1989 1955–1986 1935–1994 62 162 28 135 195 930 1960–1990 102 Cumulative incidence (%) (years) Males, 9.7% (20 years); females, 16.8% (20 years) 18% (30 years) 26.4% (40 years) 26.7% (30 years) 31.2% (30 years) Solid tumors: 11.7% (25 years) 19% (25 years) Standardized incidence ratio Males, 10.6; females, 15.4 7.7 9.4 17.9 7.7 Males, 8.41; females, 19.93 G. W. Hall et al. 292 References 1. Rubin P, Williams JP, Devesa SS, Travis LB, Constine LS (2010) Cancer genesis across the age spectrum: associations with tissue development, maintenance, and senescence. Semin Radiat Oncol 20:3–11 2. Punnett A, Tsang RW, Hodgson DC (2010) Hodgkin lymphoma across the age spectrum: epidemiology, therapy, and late effects. Semin Radiat Oncol 20:30–44 3. Hochberg J, Waxman IM, Kelly KM, Morris E, Cairo MS (2009) Adolescent non-Hodgkin lymphoma and Hodgkin lymphoma: state of the science. Br J Haematol 144:24–40 4. Foltz LM, Song KW, Connors JM (2006) Hodgkin’s lymphoma in adolescents. J Clin Oncol 24:2520–2526 5. Donaldson SS,

Hodgkin Lymphoma - A Comprehensive Overview (2020)

Related documents

Products

Support

Hodgkin Lymphoma - A Comprehensive Overview (2020)

Related documents

Add this document to collection(s)

Add this document to saved

Suggest us how to improve StudyLib